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Signaling in Migrating Neurons: From Molecules to Networks

Frontiers in Neuroscience

March 2011
5:28

DOI:10.3389/fnins.2011.00028

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PubMed

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Authors:

Konstantin Khodosevich

University of Copenhagen

Hannah Monyer

German Cancer Research Center

During prenatal and postnatal development of the mammalian brain, new neurons are generated by precursor cells that are located in the germinal zones. Subsequently newborn neurons migrate to their destined location in the brain. On the migrational route immature neurons interact via a series of recognition molecules with a plethora of extracellular cues. Stimuli that are conveyed by extracellular cues are translated into complex intracellular signaling networks that eventually enable neuronal migration. In this Focused Review we discuss signaling networks underlying neuronal migration emphasizing molecules and pathways that appear to be neuron-specific.

Signaling network controlling neuronal migration – the scheme is based on experimental data derived from several hundred publications. The only legible names denote network components that constitute “signaling hubs.” The scheme is legible upon downloading Figure S1 in Supplementary Material. (A) Seven hubs in the neuronal migration signaling network (shown in yellow). (B) More than 2/3 of the network connections (shown by red lines) involve hubs. Color code for molecules: yellow – signaling hubs, red – extracellular ligands/matrix components, green – transmembrane receptors/channels/transporters, etc., blue – intracellular signaling molecules, magenta – microtubule/actin-associated proteins, orange – cell nucleus components.

…

Signaling hubs in migrating neurons. (A) Dab1 signaling. (B) Cdk5 signaling. (C) Rac1 signaling. (D) FAK signaling. (E) Src signaling. (F) PI3K signaling. (G) Ras signaling. Arrow – activation, circle – interaction, T-shaped end – inhibition. Color code of molecules is the same as in Figure 1. Note that some links are indirect, for full scheme see Figure S1 in Supplementary Material.

…

Examples of signaling pathways in migrating neurons. (A) Scheme of HGF signaling (highlighted by red). (B) Scheme of signaling for neurotrophin protein family (NT-3, NT-4, NGF, BDNF; highlighted in red). (C) Calcium, neurotrophin, and Notch signaling are shown together. Arrow – activation, circle – interaction, T-shaped end – inhibition. Color code of molecules is the same as in Figure 1. Note that some links are indirect, for full scheme see Figure S1 in Supplementary Material.

…

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Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 1

FOCUSED REVIEW

published: 28 March 2011

doi: 10.3389/fnins.2011.00028

Signaling in migrating neurons: from

molecules to networks

Konstantin Khodosevich1,2* and Hannah Monyer1,2*

1 Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

2 Department of Clinical Neurobiology, Heidelberg University Medical Center, Heidelberg, Germany

During prenatal and postnatal development of the mammalian brain, new neurons are generated

by precursor cells that are located in the germinal zones. Subsequently newborn neurons migrate

to their destined location in the brain. On the migrational route immature neurons interact via a

series of recognition molecules with a plethora of extracellular cues. Stimuli that are conveyed

by extracellular cues are translated into complex intracellular signaling networks that eventually

enable neuronal migration. In this Focused Review we discuss signaling networks underlying

neuronal migration emphasizing molecules and pathways that appear to be neuron-speciﬁc.

Keywords: neuroblasts, signaling networks, neuronal-speciﬁc pathways

IntroductIon

In mammals neuronal migration is a fundamental

process in the development of nervous system.

The peripheral and central nervous system (CNS)

comprise numerous neurons that are born in vari-

ous locations during development and migrate

shorter or longer distances to their destination

site. Precise coordination of neuronal migration

is a prerequisite for the correct positioning and

subsequent wiring of neurons into functional

circuits. Impairment in migration results in

structural defects that are accompanied by severe

mental abnormalities.

In the peripheral nervous system, neuronal

precursors originate from undifferentiated neu-

ral crest cells and migrate during embryonic

development to their ﬁnal locations (Francis and

Landis, 1999; Glebova and Ginty, 2005). In the

CNS, most neurons derive from precursor cells

that reside in the ventricular zone. Projection

neurons are born in the ventricular zone of the

dorsal telencephalon and migrate radially toward

the pia (Marin and Rubenstein, 2003). On the

contrary, interneurons are born in the ventral

telencephalon, i.e., in the ventricular zone of

the medial, lateral, and caudal ganglionic emi-

nences from where they migrate tangentially to

the dorsal telencephalon (Corbin et al., 2001;

Marin and Rubenstein, 2003). Postnatally new

neurons continue to be generated in two brain

regions, namely in the subgranular zone (SGZ)

of the dentate gyrus in the hippocampus and

the subventricular zone (SVZ) of the lateral

ventricles (Lledo et al., 2006; Zhao et al., 2008).

Neuroblasts (immature neurons) in the hip-

pocampal SGZ migrate a short distance into the

granule cell layer of the dentate gyrus and inte-

grate into previously established neural circuits

(Kempermann et al., 2004). Neuroblasts originat-

ing in the SVZ migrate over long distances via the

rostral migratory stream to the olfactory bulb,

where they mature into granule or periglomeru-

lar neurons (Lledo and Saghatelyan, 2005; Alonso

et al., 2006). Under pathological conditions, neu-

roblasts generated in the SVZ migrate also into

injured cortex and striatum (Parent et al., 2002;

Kreuzberg et al., 2010). On the migratory route,

neuroblasts receive different stimuli from extra-

cellular cues that are paramount in migration

guiding. As a result, a number of intracellular

signaling molecules are activated. Ultimately, all

signaling pathways are integrated in a “master

network” that controls the ﬁnal intracellular out-

put in response to all extracellular inputs and

modiﬁes the cytoskeleton machinery accordingly

resulting in neuroblast migration.

Edited by:

Seth G. N. Grant, The Wellcome Trust

Sanger Institute, UK

Reviewed by:

Seth G. N. Grant, The Wellcome Trust

Sanger Institute, UK

Peter C. Kind, University of Edinburgh,

*Correspondence:

Konstantin Khodosevich graduated from

Lomonosov Moscow State University and

completed his PhD in human genetics at

the Institute of Bioorganic Chemistry,

Moscow. After his move to the lab of

Hannah Monyer, he started work on the

role of interneurons in higher brain

function. He is currently a senior scientist

in Hannah Monyer’s lab where he focuses

on signaling networks in the nervous

system during postnatal and prenatal

development.

k.khodosevich@dkfz-heidelberg.de;

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 2

SpecIfIc SIgnalIng for neuronal

mIgratIon

An ever-growing number of studies on neuronal

migration employing by and large anatomical

techniques goes back to the 1960s. Starting in the

1980s, the function of particular genes/proteins in

neuronal migration became the focus of numer-

ous experimental investigations. Whilst these

valuable studies have identiﬁed important players

in migration, many of which were cytoskeleton

proteins, during the last decade the interest grew

in identifying whole pathways and understanding

their complex interactions.

In a recent study (Khodosevich et al., 2009)

using microarray gene expression analysis we

identiﬁed several intracellular signaling pathways

underlying neuroblast migration. The identi-

ﬁed pathways were corroborated and further

expanded using bioinformatics analysis derived

from mining of public data that also included

information obtained in other cell-types and

species (see Data mining for signaling pathway

analysis). This powerful approach allows ﬁlling

in of gaps and proposing whole pathways that

would be difﬁcult to identify if one used experi-

mental data from one system only. Needless to

say, the signaling components resulting from

bioinformatics analysis can and should be tested

experimentally to provide functional proof for

their involvement in a speciﬁc system (in our

study it was murine neuroblasts migrating in

the rostral migratory stream). For this Focused

Review we used only data obtained in studies on

mammalian neuronal migration to generate a sig-

naling network whose components are discussed

in more detail. The ultimate goal is to eventually

arrive at a unique intracellular network under-

lying signaling in migrating neuroblasts. Here

we collected published data for all subtypes of

migrating neuroblasts regardless of their birth-

place (prenatal ganglionic eminences, postnatal

SVZ, precursors of peripheral nervous system,

etc.), mode of migration (radial and tangential

migration; migration in cell chains and individual

cell migration). We also used data obtained in

vitro including neurite outgrowth studies. Clearly,

each subtype of migrating neuroblasts has its

own signaling components that are “tuned” to

the microenvironment (i.e., available extracellu-

lar stimuli) of migration. Furthermore, different

modes of neuroblast migration might rely more

on one type of molecular cues in microenviron-

ment than the other, e.g., soluble factors, mem-

brane-bound receptors, or extracellular matrix.

However, subtypes of migrating neuroblasts share

the majority of intracellular signaling compo-

nents that integrate external stimuli and result

in appropriate output. With the increasing avail-

ability of experimental data it will be eventually

possible to perform a similar analysis focusing on

distinct types of migration and investigate shared

and speciﬁc molecules and their connections.

HubS In a SIgnalIng network

controllIng neuronal mIgratIon

In Figure 1 we summarize the results derived from

several hundred studies focusing on some aspects

of signaling that control neuronal migration/neu-

rite outgrowth (the names of the individual com-

ponents are legible upon downloading of Figure

S1 in Supplementary Material). The main feature

of the signaling network is the uneven distribu-

tion of connections between individual molecules

resulting in clustering of connections. Seven key

“hubs” (shown in yellow) of intracellular sign-

aling involve 2/3 of the connections within the

network (Figures 1A,B). Such network clustering

is typical for signaling networks and was shown

in many proteomic studies (see, e.g., Giot et al.,

2003; Pocklington et al., 2006). These signaling

hubs control the input and output of the network:

cell division protein kinase 5 (Cdk5), disabled

homolog 1 (Dab1), ras-related C3 botulinum

toxin substrate 1 (Rac1), focal adhesion kinase

(FAK), rat sarcoma (Ras), Rous sarcoma onco-

gene (Src), and phosphatidylinositol 3 kinase

(PI3K). Based on their connectivity resulting from

our analysis, seven hubs can be further subdivided

into two groups: Cdk5, Dab1, and Rac1 having

each 13–14 connections, while FAK, Ras, Src, and

PI3K having 7–9 connections.

While the small GTPase Rac1 and to a much

lesser extent Cdk5 kinase are involved in migra-

tion of non-neuronal cell-types, Dab1 is a spe-

ciﬁc component of neuronal migration signaling

(Bielas et al., 2004; Ayala et al., 2007). Dab1 is

a cytoplasmic adaptor molecule that was ﬁrst

described as a binding partner of the Src family

kinases Src and Fyn (Howell et al., 1997). Later its

action was also linked to Reelin signaling (Bielas

et al., 2004). However, Dab1 is involved in neuro-

nal migration not only as a target in Reelin signal-

ing, but also in amyloid precursor protein (APP;

Young-Pearse et al., 2010) and integrin signaling

(Dulabon et al., 2000; Figure 2A). Furthermore,

Dab1 is connected to other pathways via Cdk5

and Src kinases (Keshvara et al., 2002; Bock et al.,

2003; Kuo et al., 2005; Figure 2A). Since Dab1 also

directly binds to several microtubule-associated

proteins – Lis1, DISC1, and CRMP (Assadi et al.,

2003; Yamashita et al., 2006; Young-Pearse et al.,

2010) – it is a strong candidate that “tunes” com-

mon mechanisms of cell migration to neuron-

speciﬁc migration (Figure 2A).

*Correspondence:

Hannah Monyer got her MD at the

University of Heidelberg, Germany. She

was a postdoctoral fellow at Stanford

University, USA and ZMBH, Germany.

Since 1999, she is Professor and Head of

the Department of Clinical Neurobiology

at the Medical Center Heidelberg

University, and since 2010 also Professor

at the German Cancer Research Center,

Heidelberg. The studies of Hannah

Monyer’s lab aim at understanding

molecular and cellular mechanisms

underlying synchronous network

oscillations, learning, and memory with

particular focus on the functional

characterization of GABAergic

interneurons.

monyer@urz.uni-hd.de

Subventricular zone

Germinal zone in the postnatal brain in

many mammals. Spans a few

intermixed cell layers located in the

lateral wall of the paired lateral

ventricles. Contains slow-dividing

neural stem cells, fast-dividing

transit-amplifying precursors,

neuroblasts, and a few other support

cell-types.

Neuroblasts

Immature neurons with a small cell

body and usually one leading neurite.

Neuroblasts migrate by protruding

neurite and then pulling cell body in the

direction of migration.

Rostral migratory stream

Stream of migrating neuroblasts from

the subventricular zone to the olfactory

bulb. Identiﬁed in many mammals

including rodents, sheep, and primates.

Small GTPases

GTP/GDP-binding proteins. They are

active when bound to GTP and inactive

when bound to GDP. Exchange of GDP

with GTP (=activation) is catalyzed by

proteins called “guanine nucleotide

exchange factors” (GEFs). GTP

hydrolysis (=inactivation) is catalyzed

by “GTPase-activating proteins”

(GAPs).

Kinases

Enzymes that add phosphate groups

(=phosphorylate) to other proteins or

to themselves. Phosphorylation can

result in activation or inhibition of the

recipient protein.

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 3

PI3K

A B

Dab1

Ras

Src FAK

Cdk5

Rac1

Microtubules

PI3K Dab1

Ras

Src FAK

Cdk5

Rac1

Microtubules

Actin filaments Actin filaments

FIGURE 1 | Signaling network controlling neuronal migration – the scheme

is based on experimental data derived from several hundred publications.

The only legible names denote network components that constitute “signaling

hubs.” The scheme is legible upon downloading Figure S1 in Supplementary

Material. (A) Seven hubs in the neuronal migration signaling network (shown in

yellow). (B) More than 2/3 of the network connections (shown by red lines)

involve hubs. Color code for molecules: yellow – signaling hubs, red –

extracellular ligands/matrix components, green – transmembrane receptors/

channels/transporters, etc., blue – intracellular signaling molecules, magenta –

microtubule/actin-associated proteins, orange – cell nucleus components.

Cullin 5

Fbxw7

SOCS

CIN85

Dab 1

Nova2

PI3K

splicing

Dab1

AAAA

PI3K

Src

Eph

TrkB

Src

Crk/CrkL

Notch-ICD

Microtubules

DISC1

DCX

Fyn

APP

Fyn

CDKL5

PKCζ

Cdk5 Cdk5

FAK

EGFR receptors,

cell adhesion

molecules

CRMP1/2

Pctaire-1

p27kip 1 Pak1

c-Abl

Neurabin-1

Dixdc1Ndel1

DCX Tau

p35

p39

ERK1/2

MEKK

(DSLK,MEKK4)

Microtubules

F-actin

Rac1

Ras

Raf

(R-Ras, Rap-1)

Ras

Rnd1 Notch-ICD

(R-Ras, Rap-1)

Vav2/3

Trio

Cdk5

Paxillin

P-Rex1

FARP2

Pak1

C3G

Rnd1

IQGAP1

Eph TrkB Met

receptors A/B

p27kip1

microtubule/actin

filaments-associated

proteins

G-protein

other

kinases

guanine nucleotide

exchange factors (GEFs)

ubiquitin ligases

transcriptional

regulators

degraded

proteins

chemicals

small GTPases

Wave1

srGAP

Cortactin

PIP3

Dab 1

Lis1

Notch1

degraded

Dab1

degraded

FAK PIP2 PIP3

Dab1

degraded

Met

TrkB

receptors A/B

N-syndecan

EGFR ApoER2

CB1R

Integrins DCC

L1/ CHL1

ApoER2 VLDLR Integrins

GFRα1

NCAM Plexin-A/B Trkc

Plexin-A/B

TrkA

A B C

D E F G

Dab1

Ras

VLDLR

FIGURE 2 | Signaling hubs in migrating neurons. (A) Dab1 signaling. (B) Cdk5 signaling. (C) Rac1 signaling. (D) FAK signaling. (E) Src signaling. (F) PI3K signaling.

(G) Ras signaling. Arrow – activation, circle – interaction, T-shaped end – inhibition. Color code of molecules is the same as in Figure 1. Note that some links are

indirect, for full scheme see Figure S1 in Supplementary Material.

Other central hubs in the signaling net-

work of neuronal migration are Cdk5 and

Rac1 (Figures 2B,C, respectively). Although

Cdk5 was mentioned also in the context of

non- neuronal cell migration, most evidence

for its role in migration has been derived from

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 4

they receive input from many receptors, such as

DCC, L1, integrins, Reelin receptors ApoER2

and VLDLR, EGFR, TrkB, etc. (see Figure S1 in

Supplementary Material). Independent of their

individual activation, these kinases can interact

with each other resulting in FAK activation by Src

(Kuo et al., 2005). FAK and Src operate upstream

of the major cytoskeleton-linked hubs, Cdk5 and

Rac1. There is only limited evidence for a direct

connection between Src and the cytoskeleton in

migrating neurons. It involves the phosphoryla-

tion of cortactin, an actin-binding protein, by Src

(Hienola et al., 2006).

Interestingly, two other hubs, namely PI3K and

Ras, that are importantly involved in migration

of other cell-types are not that heavily connected

within the signaling network in migrating neu-

rons (Figures 2F,G, respectively). PI3K is a kinase

involved in numerous cell processes. However, in

neuronal migration signaling PI3K is activated

only by growth factor receptors and it is also a

downstream effector of Dab1 (Figure 2F). The

same holds true for Ras, with an addition of

semaphorin signaling (Figure 2G), in particular

if one takes into account that in our scheme Ras

stands for the whole protein family comprising

about 30 members. Direct involvement in neu-

ronal migration was demonstrated for two Ras

family members, R-Ras and Rap1 (Oinuma et al.,

2004; Toyofuku et al., 2005; Voss et al., 2008). Such

limited involvement of PI3K and Ras activity in

migrating neurons can hardly be explained by

a scarcity of study – these are well-known sig-

naling molecules, which have been studied for

decades. Most likely, PI3K and Ras have major

roles in growth factor and semaphorin signal-

ing while in other signaling cascades they play a

minor role (Figures 2F,G, see also Figure S1 in

Supplementary Material for full scheme).

neuronal-SpecIfIc SIgnalIng patHwayS

Signaling network in migrating neuroblasts is

complex and consists of hundreds interconnected

molecules that have been identiﬁed already and

yet more to be added to this list (Figure 1 and

Figure S1 in Supplementary Material). However,

the complexity can be reduced when focusing on a

speciﬁc stimulus (e.g., HGF or hepatocyte growth

factor; Figure 3A) or a group of similar stimuli

(e.g., all four members of neurotrophin protein

family; Figure 3B). Distinct extracellular stimuli

activate only one or a few subsets/pathways of the

signaling network in migrating neuroblasts and

some signaling pathways are speciﬁc for migrating

neurons. Most notable neuronal-speciﬁc exam-

ples are those that involve calcium, neurotrophin,

and Notch signaling (Figure 3C).

studies focusing on neuronal migration. Thus,

this signaling hub can be considered by and

large neuron-speciﬁc (Gupta and Tsai, 2003;

Nikolic, 2004). Conversely, Rac1 is a signal-

ing component of many migratory cell-types

(Fukata et al., 2003). In neurons almost all

extracellular migratory stimuli, such as Slit,

integrins, laminins, semaphorins, Reelin, GDNF,

EGF, neurotrophin-3 (NT-3), neurotrophin-4

(NT-4), brain-derived neurotrophic factor

(BDNF), netrin, calcium, etc. (see Figure S1 in

Supplementary Material), eventually converge

on these two intracellular proteins. Both hubs

are directly connected to microtubules and actin

ﬁlaments (Figures 2B,C). Thus, the convergence

of activating and inhibitory signals onto Cdk5

and Rac1 confers them a pivotal role in deter-

mining the direction and speed of neuronal

migration. Cdk5/Rac1 are also key players in

controlling the initiation and stop of migration.

Cdk5 and Rac1 activation is modulated by

other signaling molecules. Cdk5 is phosphor-

ylated and thus activated by p35, p39, and c-Abl

(Zukerberg et al., 2000; Keshvara et al., 2002;

Beffert et al., 2004; Zhao et al., 2009). However,

the regulation of these proteins that modulate

Cdk5 activity in migrating neurons has not been

explored much so far. Whilst it was shown that

PKCδ and Pctaire-1 regulate p35 activity (Cheng

et al., 2002; Zhao et al., 2009), there is no informa-

tion regarding the identity of molecules operating

upstream of p39. c-Abl tyrosine kinase, known

to be involved in migration of other cell-types

as well, exerts its action in neuronal migration

downstream of Slit/Robo signaling (Rhee et al.,

2002). Thus, modulation of Cdk5 in migrating

neurons remains to be explored.

Rac1 is a small GTPase whose activity is trig-

gered by guanine nucleotide exchange factors

(GEFs) and inhibited by GTPase-activating pro-

teins (GAPs; Figure 2C). Four GEFs activate Rac1

in migrating neurons – Vav2/3, FARP2, Trio, and

P-Rex1 (Schmid et al., 2004; Toyofuku et al., 2005;

Yoshizawa et al., 2005; Khodosevich et al., 2009;

Peng et al., 2010), but only one GAP inactivates it

– Slit–Robo GAP (srGAP; Wong et al., 2001). The

discrepancy in inhibitory and activating inputs

can be explained to some extent that activating

signaling is easier to detect. However, it is very

likely that there are other, still to be identiﬁed

GAPs that inactivate Rac1 in migrating neurob-

lasts. Interestingly, Rac1 activity is also modu-

lated by PKCζ, a kinase critically involved in the

neuronal polarization (Khodosevich et al., 2009;

Khodosevich and Monyer, 2010).

Amongst the less connected hubs, FAK and Src

are noteworthy (Figures 2D,E, respectively) since

Data mining for signaling pathway

analysis

Analysis of published data to connect

many molecules, usually obtained after

microarray search, in signaling

pathways. Data mining is performed

with the help of bioinformatics software

searching in published literature for

pairs of genes/proteins in the same

article/abstract/sentence, with/without

linking words, such as activation/

inhibition, etc.

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 5

RhoA

Cdc42

Rac1

Ras

NT-3

BDNF

Somatostatin

NT-3

NGF

NT-3

NT-4

NMDA

VGCC

NMDA

AMPA

Gluk5

NKCC1

CaMKIV

Notch-ICD

Fbxw7

IQGAP1

ADAM10

CaM

IQGAP1

presenilin

Wave1

N-WASP

Ndel 1

CaMKIV

CDKL5

CaMKK2

p35

PKCδ

CaMKII

ERK1/2

MEK

CaMKIV

Raf

Cdk5

PI3K

BDNF

NT-3

BDNF

CAPS2

Notch1

degraded

F-actin

BDNF

PI3K

Dab1

Ras

Src FAK

Cdk5

Rac1

Microtubules

PI3K Dab1

Ras

Src FAK

Cdk5

Rac1

Microtubules

Dixdc1

NT-3

Ca2+Ca2+ Notch1

degraded

proteins

TrkB

secreted ligands

NT-3

BarhI1

Notch-ICD

RBP-J

Hes1,Hes5 BDNF

CREB

small GTPases

ion channels kinases

ubiquitin ligases

other

microtubule/actin

filaments-associated

proteins

transcriptional

regulators

receptors,

cell adhesion

molecules

AA A AA A AAA

PIP3

K+

Ca2+

CI-

CI-CI-

Ca2+ K+K+

PIP2

Delta-like/Jagged

GABA Glutamate

CI-

CI-CI-Ca2+ Ca2+

Ca2+

Ca2+ Ca2+

Ca2+

K+K+K+

K+

L, N-Ca2+

channels

K+

channels

Notch1 SSTR TrkC TrkA TrkB

Microtubules

Tau Dynein/Dynactin DCX

GABAR

chemicals

FIGURE 3 | Examples of signaling pathways in migrating neurons. (A) Scheme of

HGF signaling (highlighted by red). (B) Scheme of signaling for neurotrophin protein

family (NT-3, NT-4, NGF, BDNF; highlighted in red). (C) Calcium, neurotrophin, and

Notch signaling are shown together. Arrow – activation, circle – interaction, T-shaped

end – inhibition. Color code of molecules is the same as in Figure 1. Note that some

links are indirect, for full scheme see Figure S1 in Supplementary Material.

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 6

granule-associated protein that constitutes a

further link between calcium and neurotrophin

signaling (Sadakata et al., 2007).

In addition to its major and well-studied func-

tion in determining cell fate choice and survival,

Notch1 also plays a role in neuronal migration

(Figure 3C). Upon ligand binding and stimula-

tion, the Notch receptor gets cleaved by ADAM10

and subsequently by the presenilin 1-containing

γ-secretase complex (Louvi et al., 2004; Jorissen

et al., 2010). Notch-ICD (intracellular domain)

translocates into the nucleus to interact with

RBP-J and activates Notch-dependent transcrip-

tion of Hes1 and Hes5 (Hashimoto-Torii et al.,

2008). It is of note that the signaling hub Dab1

controls Notch-ICD degradation by inhibiting

Fbxw7, a component of the ubiquitin protein

ligase complex (Hashimoto-Torii et al., 2008).

tranScrIptIon actIvatIon In mIgratIng

neuroblaStS

Although migrating neuroblasts are still able to

proliferate, a major switch in the transcription

program between precursor cells and neurob-

lasts must take place to account for proliferation

and migration. Thus, it stands to reason that

genes involved in precursor cell proliferation are

downregulated with a concomitant upregulation

of genes responsible for migration, leading to a

dramatic change in the gene expression proﬁle.

This is supported by our previous results dem-

onstrating that around 1000 genes changed their

expression in neuroblasts that had migrated some

distance from the site of origin, the postnatal SVZ

(Khodosevich et al., 2009).

One of the most prominent transcription fac-

tors involved in the switch from precursor cells

to neuroblasts is distal-less homeobox protein

Dlx1/2 (see Figure S1 in Supplementary Material

for full scheme of transcriptional control). Dlx1/2

knockout animals exhibit strong neuronal migra-

tion defects (Cobos et al., 2007). Regulation by

Dlx1/2 include expression of a number of note-

worthy genes that are known to mediate several

fundamental processes in neuronal migration,

including repulsion/attraction, stop signal for

migration, motility, and cytoskeleton reorgani-

zation (Ghashghaei et al., 2007; Tran et al., 2007).

Whilst expression of Sema3A, Reelin, and Arx

is upregulated by Dlx1/2, that of Pak3, MAP2,

Tau, Robo1, GAP43, and Npn2 is downregulated

(Cobos et al., 2007; Le et al., 2007).

Another transcription factor, neuregulin 2

(Ngn2), downregulates the expression of the small

GTPase RhoA and upregulates the expression of

Dcx, p35, and small GTPase Rnd2 (Ge et al., 2006;

Heng et al., 2008). Dcx ( doublecortin) is a neuro-

nal-speciﬁc microtubule-associated protein that,

Studies describing intracellular signaling

mediating calcium responses in migrating neu-

rons are by and large limited to the effect of

calcium per se and calcium-dependent kinases

(Figure 3C). Calcium was shown to activate RhoA

(Guan et al., 2007) and the Rac1-activating pro-

tein IQGAP1 (Kholmanskikh et al., 2006), most

likely also through some intermediate partners.

Interestingly, while RhoA inhibits neuronal

migration, Rac1 stimulates it, clearly showing

that, depending on the upstream stimulus,

calcium-signaling can have opposite effects. The

ﬁrst calcium-signaling intermediate protein is

calmodulin (CaM) that is activated directly by

calcium binding to it. CaM in turn activates

CaMKII (Ca/calmodulin dependent kinase II)

and CaMKK2 (Ca/calmodulin dependent kinase

kinase 2). As CaMKII can bind F-actin ﬁlaments,

it constitutes the link between calcium-signaling

and cytoskeleton remodeling (Fink et al., 2003).

CaMKK2 activates another Ca/calmodulin

dependent kinase – CaMKIV that upon activa-

tion translocates into the nucleus and upregulates

BDNF expression (Kokubo et al., 2009). Indeed,

we could recently demonstrate the involvement

of CaMKIV in the migration of neuroblasts

in the rostral migratory stream (Khodosevich

et al., 2009). These are the only intracellular

calcium-signaling components for which there

is experimental evidence that they are involved

in neuronal migration. Missing players in the

calcium-signaling network can be proposed,

but such an educated guess would rely on data

from other cell-types or model organisms. Of

the signaling hubs only Rac1 has been linked to

calcium-signaling via IQGAP1 (Kholmanskikh

et al., 2006).

The neurotrophin protein family comprises

four members, NT-3, NT-4, BDNF, and nerve

growth factor (NGF), which regulate neuronal

migration via tropomyosin-receptor-kinases

(Trk) A, B, and C (Figure 3C). All neurotrophins

activate hubs of intracellular signaling, such as

PI3K, Ras, Rac1, and Cdk5 (Yamauchi et al.,

2003; Berghuis et al., 2005; Yoshizawa et al., 2005;

Chiaramello et al., 2007), that, as discussed above,

will eventually lead to cytoskeleton remodeling.

Interestingly, already the expression and release

of the neurotrophins themselves is tightly con-

trolled during neuronal migration. As we men-

tioned above, calcium-signaling can activate

BDNF expression via CaMKIV (Kokubo et al.,

2009). The expression of neurotrophin NT-3

on the other hand is activated by the homeobox

protein Barhl1 (Li et al., 2004). On the next stage,

the release of neurotrophin-containing secretory

granules is mediated by Ca-dependent activa-

tor protein for secretion 2 (CAPS2), a secretory

Khodosevich and Monyer Signaling in migrating neuroblasts

Frontiers in Neuroscience www.frontiersin.org March 2011 | Volume 5 | Article 28 | 7

The morphological features of migrating neu-

roblasts differ from those of many other types of

migratory cells. During migrational “step” neurob-

last extends leading process in the direction con-

trolled by external stimuli, then nucleus moves into

the leading process and ﬁnally the trailing process is

retracted. The majority of cytoskeleton-associated

components are concentrated at the very tip of the

leading process – the growth cone. Hence neuro-

nal migration differs from the classical one known

in ﬁbroblasts. It is not surprising that the unique

neuroblast morphology is also reﬂected in idi-

osyncratic intracellular signaling. Thus, although

migrating neuroblasts share a signiﬁcant number

of hubs and pathways involved in the migration

of other cell-types, they are equipped with neu-

ronal-speciﬁc actors in migration that most likely

adjust the common “migratory machinery” to the

speciﬁc neuronal needs. Furthermore the weights

between certain components or even whole path-

ways within a network exhibit neuronal-speciﬁcity.

It may be that these neuronal-speciﬁc pathways in

migration are not only critical for neuroblasts get-

ting to the right place but are already a prerequisite

for neuronal connectivity.

acknowledgmentS

Images were made with the use of vector graphics

from DragonArtz Designs (www.dragonartz.net).

The work was supported in part by the Schilling

Foundation, DFG (SFB488 grant), and BMBF

(RUS 09/B38).

Supplementary materIal

The Supplementary Material for this article can

be found online at http://www.frontiersin.org/

Neuroscience/10.3389/fnins.2011.00028/abstract

Figure S1 | Full scheme of signaling network

controlling neuronal migration. The scheme was

generated by using published data regarding neu-

ronal migration/neurite outgrowth in mammals

only (i.e., excluding other cell-types and model

organisms). See full list of literature in the main

manuscript and supplementary references. Note

that we excluded some molecules that were shown

to be involved in neuronal migration/neurite out-

growth, but their intracellular partners are not

known in migrating neuroblasts. Color code of

molecules: yellow – signaling hubs, red – extracel-

lular ligands/matrix components, green – trans-

membrane receptors/channels/transporters, etc.,

blue – intracellular signaling molecules, magenta

– microtubule/actin-associated proteins, orange

– cell nucleus components. Arrow – activation,

circle – interaction, T-shaped end – inhibition.

Some links are indirect due to scarcity of pub-

lished data.

together with Dcx-like kinase (Dcxl), is required

for proper microtubule remodeling in response to

migratory stimuli (Friocourt et al., 2007). Rnd2

and p35 activate RhoA and Cdk5, respectively

(Keshvara et al., 2002; Beffert et al., 2004; Tanaka

et al., 2006; Heng et al., 2008). Since RhoA and

Cdk5 have opposite functions in the regulation of

neuronal migration, precise control of their sign-

aling by Ngn2 is very important (also taking into

account that RhoA expression per se is regulated

by Ngn2). Which other factors may interact with

Ngn2 and specify stimulation of either RhoA or

Cdk5 signaling remains to be determined.

Cooperation between transcription factor

E2F3 and retinoblastoma (Rb) results in the

inhibited expression of several genes, including

Reelin receptor VLDLR (McClellan et al., 2007).

Reelin is one of the major extracellular ligands

controlling several stages of neuronal migra-

tion. Knockout of Reelin or any of its receptors

cause various defects in brain formation due to

impaired neuronal migration during embryonic

development (Assadi et al., 2003; Hack et al.,

2007).

Finally, other mechanisms than conventional

transcription factors that regulate gene expression

in migrating neuroblasts should be mentioned.

Thus, actin per se controls its own expression via

a negative feedback loop. There are two types

of actin in migrating neurons – polymerized,

F-actin, and depolymerized or free, G-actin.

When in excess, free G-actin translocates into

the nucleus and downregulates the expression of

actin by inhibiting the expression of the transcrip-

tion factor MRTF (myocardin family transcrip-

tion factor) that together with serum response

factor (SRF) controls actin expression (Stern

et al., 2009).

Posttranscriptional RNA processing is also

subject to regulation in migrating neuroblasts.

For instance, alternative splicing of the key sign-

aling hub Dab1 is regulated by the RNA-binding

protein Nova2 preventing the inclusion of two

additional exons (Yano et al., 2010), which is nec-

essary for correct migration of cortical neurons

during development.

Last but not least, as already mentioned above,

calcium and Notch signaling are involved in regu-

lation of transcription in neuroblasts.

concluSIon

This study and others (see, e.g., Lee and Megeney,

2005; Pocklington et al., 2006) using similar

approaches clearly highlight how complex sign-

aling in different systems (e.g., migrating neurons,

synapse signaling, yeast kinase signaling) can be

reduced to major components eventually leading

to the identiﬁcation of general network principles.

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authors declare that the research

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of interest.

Received: 17 November 2010; paper pend-

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NBS1 interacts with Notch signaling in neuronal homeostasis

Article

Full-text available

Aug 2020

NBS1 is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM-and ATR-mediated DNA damage response (DDR) pathways. Mutations in NBS1 cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), of which neuronal deficits, including microcephaly and intellectual disability, are classical hallmarks. Given its function in the DDR to ensure proper proliferation and prevent death of replicating cells, NBS1 is essential for life. Here we show that, unexpectedly, Nbs1 deletion is dis-pensable for postmitotic neurons, but compromises their arborization and migration due to dysregulated Notch signaling. We find that Nbs1 interacts with NICD-RBPJ, the effector of Notch signaling, and inhibits Notch activity. Genetic ablation or pharmaceutical inhibition of Notch signaling rescues the matu-ration and migration defects of Nbs1-deficient neu-rons in vitro and in vivo. Upregulation of Notch by Nbs1 deletion is independent of the key DDR downstream effector p53 and inactivation of each MRN component produces a different pattern of Notch activity and distinct neuronal defects. These data indicate that neuronal defects and aberrant Notch activity in Nbs1-deficient cells are unlikely to be a direct consequence of loss of MRN-mediated DDR function. This study discloses a novel function of NBS1 in crosstalk with the Notch pathway in neuron development .

The impact of maternal immune activation on embryonic brain development

Article

Full-text available

Mar 2023

The adult brain is a complex structure with distinct functional sub-regions, which are generated from an initial pool of neural epithelial cells within the embryo. This transition requires a number of highly coordinated processes, including neurogenesis, i.e., the generation of neurons, and neuronal migration. These take place during a critical period of development, during which the brain is particularly susceptible to environmental insults. Neurogenesis defects have been associated with the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder and schizophrenia. However, these disorders have highly complex multifactorial etiologies, and hence the underlying mechanisms leading to aberrant neurogenesis continue to be the focus of a significant research effort and have yet to be established. Evidence from epidemiological studies suggests that exposure to maternal infection in utero is a critical risk factor for NDDs. To establish the biological mechanisms linking maternal immune activation (MIA) and altered neurodevelopment, animal models have been developed that allow experimental manipulation and investigation of different developmental stages of brain development following exposure to MIA. Here, we review the changes to embryonic brain development focusing on neurogenesis, neuronal migration and cortical lamination, following MIA. Across published studies, we found evidence for an acute proliferation defect in the embryonic MIA brain, which, in most cases, is linked to an acceleration in neurogenesis, demonstrated by an increased proportion of neurogenic to proliferative divisions. This is accompanied by disrupted cortical lamination, particularly in the density of deep layer neurons, which may be a consequence of the premature neurogenic shift. Although many aspects of the underlying pathways remain unclear, an altered epigenome and mitochondrial dysfunction are likely mechanisms underpinning disrupted neurogenesis in the MIA model. Further research is necessary to delineate the causative pathways responsible for the variation in neurogenesis phenotype following MIA, which are likely due to differences in timing of MIA induction as well as sex-dependent variation. This will help to better understand the underlying pathogenesis of NDDs, and establish therapeutic targets.

A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy

Article

Full-text available

Mar 2021

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.

Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain

Article

Full-text available

Jan 2021

Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+ signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.

Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells

Article

Jan 2020

Cell therapy raises high hopes for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from two distant embryonic SCs lines (H9 and RC17) to express one of four prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, three out of four modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation towards neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.

Prenatal Environment That Affects Neuronal Migration

Article

Full-text available

Jul 2019

Migration of neurons starts in the prenatal period and continues into infancy. This developmental process is crucial for forming a proper neuronal network, and the disturbance of this process results in dysfunction of the brain such as epilepsy. Prenatal exposure to environmental stress, including alcohol, drugs, and inflammation, disrupts neuronal migration and causes neuronal migration disorders (NMDs). In this review, we summarize recent findings on this topic and specifically focusing on two different modes of migration, radial, and tangential migration during cortical development. The shared mechanisms underlying the NMDs are discussed by comparing the molecular changes in impaired neuronal migration under exposure to different types of prenatal environmental stress.

Functional enrichment analysis based on long noncoding RNA associations

Article

Full-text available

Apr 2018
BMC SYST BIOL

Background: Differential gene expression analysis using RNA-seq data is a popular approach for discovering specific regulation mechanisms under certain environmental settings. Both gene ontology (GO) and KEGG pathway enrichment analysis are major processes for investigating gene groups that participate in common biological responses or possess related functions. However, traditional approaches based on differentially expressed genes only detect a few significant GO terms and pathways, which are frequently insufficient to explain all-inclusive gene regulation mechanisms. Methods: Transcriptomes of survivin (birc5) gene knock-down experimental and wild-type control zebrafish embryos were sequenced and assembled, and a differential expression (DE) gene list was obtained for traditional functional enrichment analysis. In addition to including DE genes with significant fold-change levels, we considered additional associated genes near or overlapped with differentially expressed long noncoding RNAs (DE lncRNAs), which may directly or indirectly activate or inhibit target genes and play important roles in regulation networks. Both the original DE gene list and the additional DE lncRNA-associated genes were combined to perform a comprehensive overrepresentation analysis. Results: In this study, a total of 638 DE genes and 616 DE lncRNA-associated genes (lncGenes) were leveraged simultaneously in searching for significant GO terms and KEGG pathways. Compared to the traditional approach of only using a differential expression gene list, the proposed method of employing DE lncRNA-associated genes identified several additional important GO terms and KEGG pathways. In GO enrichment analysis, 60% more GO terms were obtained, and several neuron development functional terms were retrieved as complete annotations. We also observed that additional important pathways such as the FoxO and MAPK signaling pathways were retrieved, which were shown in previous reports to play important roles in apoptosis and neuron development functions regulated by the survivin gene. Conclusions: We demonstrated that incorporating genes near or overlapped with DE lncRNAs into the DE gene list outperformed the traditional enrichment analysis method for effective biological functional interpretations. These hidden interactions between lncRNAs and target genes could facilitate more comprehensive analyses.

The potential of mechanistic information organised within the AOP framework to increase regulatory uptake of the developmental neurotoxicity (DNT) in vitro battery of assays

Article

Jun 2021
REPROD TOXICOL

A major challenge in regulatory developmental neurotoxicity (DNT) assessment is lack of toxicological information for many compounds. Therefore, the Test Guidelines programme of the Organisation for Economic Cooperation and Development (OECD) took the initiative to coordinate an international collaboration between diverse stakeholders to consider integration of alternative approaches towards improving the current chemical DNT testing. During the past few years, a series of workshops was organized during which a consensus was reached that incorporation of a DNT testing battery that relies on in vitro assays anchored to key neurodevelopmental processes should be developed. These key developmental processes include neural progenitor cell proliferation, neuronal and oligodendrocyte differentiation, neural cell migration, neurite outgrowth, synaptogenesis and neuronal network formation, as well key events identified in the existing Adverse Outcome Pathways (AOPs). AOPs deliver mechanistic information on the causal links between molecular initiating event, intermediate key events and an adverse outcome of regulatory concern, providing the biological context to facilitate development of Integrated Approaches to Testing and Assessment (IATA) for various regulatory purposes. Developing IATA case studies, using mechanistic information derived from AOPs, is expected to increase scientific confidence for the use of in vitro methods within an IATA, thereby facilitating regulatory uptake. This manuscript summarizes the current state of international efforts to enhance DNT testing by using an in vitro battery of assays focusing on the role of AOPs in informing the development of IATA for different regulatory purposes, aiming to deliver an OECD guidance document on use of in vitro DNT battery of assays that include in vitro data interpretation.

Pro-opiomelanocortin (POMC) neuron translatome signatures underlying obesogenic gestational malprogramming in mice

Article

Full-text available

Feb 2020

Objective Maternal unbalanced nutritional habits during embryonic development and perinatal stages perturb hypothalamic neuronal programming of the offspring, thus increasing obesity-associated diabetes risk. However, the underlying molecular mechanisms remain largely unknown. In this study we sought to determine the translatomic signatures associated with POMC neuron malprogramming in maternal obesogenic conditions. Methods We used the Ribotag mouse model to specifically profile the translatome of POMC neurons during neonatal (P0) and perinatal (P21) life and its neuroanatomical, functional and physiological consequences. Results Maternal HFD exposure did not interfere with offspring’s hypothalamic POMC neuron specification, but significantly impaired their spatial distribution and axonal extension to target areas. Importantly, we established POMC neuron-specific translatome signatures accounting for aberrant neuronal development and axonal growth. These anatomical and molecular alterations caused metabolic dysfunction in early-life and adulthood. Conclusions Our study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.

Desarrollo neuroembriológico: el camino desde la proliferación hasta la perfección

Article

Full-text available

Jul 2018

El desarrollo neurológico humano requiere una serie de pasos que permitan orientar, regular y diferenciar los diversos componentes cerebrales, para así garantizar, de una manera bastante precisa, la correcta organización y funcionamiento de las estructuras neuronales. La neurogénesis está clásicamente dividida en cuatro etapas consecutivas: proliferación, migración, diferenciación y maduración. En los humanos,estas ocurren desde la tercera semana de gestación hasta la vida adulta y precisan de un complejo grupo de paquetes genéticos, así como de algunos factores asociados, que se han ido descubriendo gracias a los avances en la biología molecular. El artículo es una revisión acerca del desarrollo neuroembriológico humano y los componentes genéticos más relevantes encontrados en la literatura.

Biocemical and Functional Interaction of Disrupted-in-Schizophrenia 1 and Amyloid Precursor Protein Regulates Neuronal Migration during Mammalian Cortical Development

Article

Full-text available

Aug 2010
J NEUROSCI

Although clinically distinct, schizophrenia and Alzheimer's disease are common and devastating disorders that profoundly impair cognitive function. For Alzheimer's disease, key mechanistic insights have emerged from genetic studies that identified causative mutations in amyloid precursor protein (APP) and presenilin. Several genes have been associated with schizophrenia and other major psychoses, and understanding their normal functions will help elucidate the underlying causes of these disorders. One such gene is disrupted-in-schizophrenia 1 (DISC1). DISC1 and APP have been implicated separately in cortical development, with each having roles in both neuronal migration and neurite outgrowth. Here, we report a previously unrecognized biochemical and functional interaction between DISC1 and APP. Using in utero electroporation in the living rat brain, we show that DISC1 acts downstream of APP and Disabled-1 to regulate cortical precursor cell migration. Specifically, overexpression of DISC1 rescues the migration defect caused by a loss of APP expression. Moreover, knockdown of APP in cultured embryonic neurons results in altered subcellular localization of DISC1. Using transfected cells and normal brain tissue, we show that APP and DISC1 coimmunoprecipitate and that the intracellular domain of APP interacts with the N-terminal domain of DISC1. Based on these findings, we hypothesize that the APP cytoplasmic region transiently interacts with DISC1 to help regulate the translocation of DISC1 to the centrosome, where it plays a key role in controlling neuronal migration during cortical development.

Trio Is a Key Guanine Nucleotide Exchange Factor Coordinating Regulation of the Migration and Morphogenesis of Granule Cells in the Developing Cerebellum

Article

Full-text available

Aug 2010
J BIOL CHEM

Orchestrated regulation of neuronal migration and morphogenesis is critical for neuronal development and establishment of functional circuits, but its regulatory mechanism is incompletely defined. We established and analyzed mice with neural-specific knock-out of Trio, a guanine nucleotide exchange factor with multiple guanine nucleotide exchange factor domains. Knock-out mice showed defective cerebella and severe signs of ataxia. Mutant cerebella had no granule cells in the internal granule cell layer due to aberrant granule cell migration as well as abnormal neurite growth. Trio-deficient granule cells showed reduced extension of neurites and highly branched and misguided processes with perturbed stabilization of actin and microtubules. Trio deletion caused down-regulation of the activation of Rac1, RhoA, and Cdc42, and mutant granule cells appeared to be unresponsive to neurite growth-promoting molecules such as Netrin-1 and Semaphorin 6A. These results suggest that Trio may be a key signal module for the orchestrated regulation of neuronal migration and morphogenesis during cerebellar development. Trio may serve as a signal integrator decoding extrinsic signals to Rho GTPases for cytoskeleton organization.

The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex

Article

Full-text available

Apr 2010
J NEUROSCI

The metalloproteinase and major amyloid precursor protein (APP) alpha-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors. Adam10(-/-) mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. To investigate the function of ADAM10 in brain, we generated Adam10 conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived from Adam10 cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. We found that Notch-1 processing was affected, leading to downregulation of several Notch-regulated genes in Adam10 cKO brains, in accordance with the central role of ADAM10 in this signaling pathway and explaining the neurogenic phenotype. Finally, we found that alpha-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP alpha-secretase in brain. Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP.

Signaling involved in neurite outgrowth of postnatally born subventricular zone neurons in vitro

Article

Full-text available

Feb 2010
BMC NEUROSCI

Neurite outgrowth is a key process during neuronal migration and differentiation. Complex intracellular signaling is involved in the initiation of neurite protrusion and subsequent elongation. Although, in general many constituents of the machinery involved in this multi-stage process are common for neurons in distinct brain areas, there are notable differences between specific neuronal subtypes. We analyzed key intracellular components of neurite outgrowth signaling in postnatally born subventricular zone (SVZ) neurons in vitro. We showed that inhibitors of PI3K, Akt1, PKCzeta and small GTPases significantly reduced neurite outgrowth. Transfection of SVZ-derived neurons with inactive forms of Rac1 or Cdc42 also decreased neurite length whereas transfection with constitutively active forms of Rac1, Cdc42 or Akt1 as well as with full-length PI3K or PKCzeta increased neurite length. PI3K, Akt1 and PKCzeta acted upstream of the small GTPases Rac1 and Cdc42, which in turn modulate lamellipodia formation of SVZ-derived neurons. We showed the involvement of PI3K/Akt1/PKCzeta/Rac1/Cdc42 pathway in neurite outgrowth of postnatally born SVZ neurons.

PKC regulates cortical radial migration by stabilizing the Cdk5 activator p35

Article

Full-text available

Nov 2009
P NATL ACAD SCI USA

Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here, we show that PKCdelta, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKCdelta attenuated the degradation of p35 but not its mutant derivative, which could not be phosphorylated by PKCdelta. Down-regulation of PKCdelta by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by down-regulation of p35 and could be prevented by cotransfection with the wild-type but not the mutant p35. Furthermore, PKCdelta could be activated by the promigratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCdelta and p35 were required for the promigratory effect of BDNF on cultured newborn neurons. Thus, PKCdelta may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.

Selective Regulation of Neurite Extension and Synapse Formation by the ?? but not the ?? Isoform of CaMKII

Article

Jul 2003
NEURON

Neurite extension and branching are important neuronal plasticity mechanisms that can lead to the addition of synaptic contacts in developing neurons and changes in the number of synapses in mature neurons. Here we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates movement, extension, and branching of filopodia and fine dendrites as well as the number of synapses in hippocampal neurons. Only CaMKIIβ, which peaks in expression early in development, but not CaMKIIα, has this morphogenic activity. A small insert in CaMKIIβ, which is absent in CaMKIIα, confers regulated F-actin localization to the enzyme and enables selective upregulation of dendritic motility. These results show that the two main neuronal CaMKII isoforms have markedly different roles in neuronal plasticity, with CaMKIIα regulating synaptic strength and CaMKIIβ controlling the dendritic morphology and number of synapses.

Reelin Binds α3β1 Integrin and Inhibits Neuronal Migration

Article

Jul 2000
NEURON

Mice that are mutant for Reelin or Dab1, or doubly mutant for the VLDL receptor (VLDLR) and ApoE receptor 2 (ApoER2), show disorders of cerebral cortical lamination. How Reelin and its receptors regulate laminar organization of cerebral cortex is unknown. We show that Reelin inhibits migration of cortical neurons and enables detachment of neurons from radial glia. Recombinant and native Reelin associate with α3β1 integrin, which regulates neuron–glia interactions and is required to achieve proper laminar organization. The effect of Reelin on cortical neuronal migration in vitro and in vivo depends on interactions between Reelin and α3β1 integrin. Absence of α3β1 leads to a reduction of Dab1, a signaling protein acting downstream of Reelin. Thus, Reelin may arrest neuronal migration and promote normal cortical lamination by binding α3β1 integrin and modulating integrin-mediated cellular adhesion.

Signal Transduction in Neuronal Migration

Article

Oct 2001

Kit Wong

The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo). We report here that the intracellular domain of Robo interacts with a novel family of Rho GTPase activating proteins (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions responsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) of the forebrain. A constitutively active Cdc42 blocked the repulsive effect of Slit. These results have demonstrated important roles for GAPs and Cdc42 in neuronal migration. We propose a signal transduction pathway from the extracellular guidance cue to intracellular actin polymerization.

Increased subventricular zone-derived cortical neurogenesis after ischemic lesion

Article

Nov 2010
EXP NEUROL

In adult rodents stroke enhances neurogenesis resulting in the addition of neurons to forebrain regions such as striatum or cortex where postnatal neurogenesis under normal conditions plays a negligible role. In the cortex, new neurons are generated either from local cortical precursors that are activated by stroke or from precursors residing in the subventricular zone (SVZ) of lateral ventricles that under normal conditions supply neuroblasts by and large only for the olfactory bulb. In this study we used 5HT3A-EGFP transgenic mice in which all neuroblasts originating in the SVZ are EGFP-labeled. We induced stroke in these mice and by combination of EGFP detection with BrdU injections we labeled all post-stroke-generated SVZ-derived neuroblasts. We showed an increase in SVZ-derived neuroblasts 14 and 35 days after stroke in the ipsilateral hemisphere. Post-stroke-generated SVZ-derived neuroblasts migrated to the cortex and survived for at least 35 days representing 2% of BrdU-positive cells in peri-infarct area where they differentiate into mature neurons. Thus, stroke enhances SVZ neurogenesis and attracts newborn neurons to the injury zone.

Nova2 Regulates Neuronal Migration through an RNA Switch in Disabled-1 Signaling

Article

Jun 2010

Neuronal migration leads to a highly organized laminar structure in the mammalian brain, and its misregulation causes lissencephaly and behavioral and cognitive defects. Reelin signaling, which is mediated in part by a key adaptor, disabled-1 (Dab1), plays a critical but incompletely understood role in this process. We found that the neuron-specific RNA-binding protein Nova2 regulates neuronal migration in late-generated cortical and Purkinje neurons. An unbiased HITS-CLIP and exon junction array search for Nova-dependent reelin-pathway RNAs at E14.5 revealed only one candidate-an alternatively spliced isoform of Dab1 (Dab1.7bc). In utero electroporation demonstrated that Dab1.7bc was sufficient to induce neuronal migration defects in wild-type mice and exacerbate defects when Dab1 levels were reduced, whereas Dab1 overexpression mitigates defects in Nova2 null mice. Thus, Nova2 regulates an RNA switch controlling the ability of Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new links between splicing regulation, brain disease, and development.

Signaling in Migrating Neurons: From Molecules to Networks

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