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The human brain is a complex structure that controls
sophisticated cognitive behaviour. Anatomically,
the cerebral cortex is divided into frontal, temporal,
parietal and occipital lobes, and these regions control
thinking, language, movement, sensation, vision and
other functions. The formation of these distinct func-
tional regions during cortical development is called
regionalization (or arealization)
1–4
. Two models for
the formation of cortical functional regions have been
proposed
5–7
. The protomap model suggests that intrinsic
signals from the ‘proliferative units’ in the ventricular
zone regulate functional regionalization, whereas the
protocortex model argues the importance of extrinsic
influences, such as the thalamocortical inputs
5–7
.
Accumulating evidence indicates that both models are
applicable to the regulation of cortical patterning and
the establishment of cortical regionalization
2–4
.
The cerebral cortex is also divided into left and
right hemispheres. The left hemisphere is normally
dominant for language and logical processing, whereas
the right hemisphere is specified for spatial recogni-
tion
8,9
. Additionally, the segregation of human brain
functions between the left and right hemispheres is
associated with asymmetries of anatomical structures,
such as the
Sylvian fissures and the planum tempo-
rale
10,11
. One of the striking features of motor control
in humans is that more than 90% of the population is
more skilful with the right hand, which is controlled
by the left hemisphere
12
. Similar to the left-hemi-
sphere dominance of handedness, language ability is
dominant in the left hemisphere in more than 95% of
the right-handed population but in only 70% of the
left-handed population
12
.
Is it coincidental that both language ability and
hand use are dominant in the left hemisphere in most
of humans? Is there genetic control of both brain asym-
metry and handedness? Using molecular and neuro-
logical approaches, we are beginning to tackle these
questions and discover the neurological circuitries
that regulate brain asymmetry. Here, we describe brain
asymmetries that have been measured using modern
imaging techniques and discuss the genetic correlation
between brain asymmetry and preferential hand use.
Furthermore, we propose evolutionary and molecular
mechanisms that might regulate brain asymmetry and
handedness.
Functional and anatomical brain asymmetries
The first detailed description of functional asymmetry
in the human brain was made in the 1860s by a French
doctor named Paul Broca. He found that there was a
lesion in the left hemisphere of the post-mortem brain
of a patient with a one-word vocabulary. Broca claimed
that language ability in the human brain is lateral-
ized and supplied perhaps the first strong evidence of
functional asymmetry in the brain
13
. This brain region,
which controls speech, is called
Broca’s area in honour
of his discovery. In 1874, a German neurologist named
Carl Wernicke discovered that damage to a region of
the left hemisphere could cause a type of aphasia that
resulted in an impairment of language comprehension
14
.
This area is called
Wernicke’s area.
Brain functional asymmetry is not limited to lan-
guage ability. Whereas the right cerebral cortex regu-
lates movement of the left side of the body (and the left
cerebral cortex regulates movement of the right side),
*Department of Cell and
Developmental Biology,
Cornell University Weill
Medical College, Box 60,
W820A, 1300 York Avenue,
New York 10021, USA.
‡
Department of Neurology,
Howard Hughes Medical
Institute, Beth Israel
Deaconess Medical Center,
New Research Building Room
0266, 77 Avenue Louis
Pasteur, Boston,
Massachusetts 02115, USA.
Correspondence to T.S. or
C.A.W. e-mails:
tas2009@med.cornell.edu;
cwalsh@bidmc.harvard.edu
doi:10.1038/nrn1930
Protomap model
Proposed by Pasko Rakic. He
suggested that regionalization
is mainly controlled by
molecular determinants that
are intrinsic to the proliferative
zone of the neocortex. The
‘proliferative units’ in the
ventricular zone form a
protomap of prospective
cortical regions. Postmitotic
neurons migrating from the
ventricular zone maintain the
regional properties of the
proliferative units.
Molecular approaches to brain
asymmetry and handedness
Tao Sun* and Christopher A. Walsh
‡
Abstract | In the human brain, distinct functions tend to be localized in the left or right
hemispheres, with language ability usually localized predominantly in the left and spatial
recognition in the right. Furthermore, humans are perhaps the only mammals who have
preferential handedness, with more than 90% of the population more skilful at using the right
hand, which is controlled by the left hemisphere. How is a distinct function consistently
localized in one side of the human brain? Because of the convergence of molecular and
neurological analysis, we are beginning to consider the puzzle of brain asymmetry and
handedness at a molecular level.
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ab c
AA
R
L
R
L
R
L
DD
VV
PP
Protocortex model
Proposed by Dennis O’Leary.
He suggested that
regionalization is controlled in
large part by extrinsic
influences, such as
thalamocortical inputs.
Sylvian fissures
The deepest and most
prominent of the cortical
fissures (clefts). They separate
the frontal lobes and temporal
lobes in both hemispheres.
Broca’s area
The left inferior frontal gyrus of
the frontal lobe of the human
cortex. This area is responsible
for speech and for
understanding language.
Injuries to this area can cause
Broca’s aphasia, which is
characterized by non-fluent
speech, few words, short
sentences and many pauses.
Patients normally lose the
ability to understand or
produce grammatically
complex sentences.
Wernicke’s area
The left posterior section of the
superior temporal gyrus, where
the temporal lobe and parietal
lobe meet. It is involved in the
comprehension of written or
spoken language. People with
damage in this area speak
fluently, but often using words
or jumbled syllables that make
no sense; this is known as
Wernicke’s aphasia.
more than 90% of the human population is naturally
more skilled with the right hand than with the left
12
.
Cognitive studies on patients with unilateral lesions and
on patients with split-brain surgery have revealed many
other differences between the left and right cerebral
cortex
15
. For example, the left hemisphere is dominant
for mathematical and logical reasoning, whereas the
right hemisphere excels at shape recognition, spatial
attention, emotion processing and musical and artistic
functions
15–17
.
Using modern imaging techniques, particularly
MRI, scientists can map the asymmetries of anatomical
structures in the human brain. Among the most studied
regions are the Sylvian fissures, which separate the fron-
tal and temporal lobes. For example, the posterior end
of the Sylvian fissure in the right hemisphere is higher
than in the left, whereas the left fissure has a more gentle
slope
10,11,18
(FIG. 1a,b). The planum temporale, a region in
the posterior portion of the superior temporal sulcus, is
larger in the left hemisphere than in the right in more
than 65% of adult brains and 56–79% of fetal or infant
brains examined
19–22
. More recently, digital brain maps
have generated three-dimensional images of human
brains and further revealed cortical asymmetries
10
.
Moreover, a new population average, landmark- and
surface-based (PALS) atlas approach has shown the most
consistent asymmetries to be in and near the Sylvian
fissures
(FIG. 1a,b) and the superior temporal sulcus
11
(FIG. 1c)
.
The differences in neuronal cell type or cell
organization that might underlie these gross anatomi-
cal differences are unclear. Studies have shown that
language-related areas of the left cortex might contain
more and larger layer 3 pyramidal cells than corre-
sponding areas in the right hemisphere
23
. Rosen
24
and Galaburda
25
used histological studies to suggest
that the asymmetrical regions in the cortex might be
the results of differences in neuron numbers but not
packing density. However, the tremendous size of the
human cortex and its extensive and variable folding
pattern make corresponding areas difficult to compare
with certainty.
In addition to the asymmetries related to language
abilities, such as those of the Sylvian fissures and the pla-
num temporale, anatomical asymmetries associated with
hand use have also been detected in other regions in the
human cerebral cortex. In the primary somatosensory
cortex (S1), studies using
magnetic source imaging have
shown that the cortical representation of the right hand
is larger than the one of the left hand in right-handers,
and vice versa in left-handers
26
. Moreover, the left central
sulcus, a large inward fold marking the division between
the frontal and parietal lobes, is deeper than the right
central sulcus in right-handers
27
. Inter-hemispheric
comparison has further revealed a significant increase
of the hand and finger movement representation in the
primary motor cortex opposite to the preferred hand
28
.
In contrast to these findings, other reports have
shown no obvious correlation of handedness and brain
asymmetries. For example, using voxel-based morpho-
metry, Good et al.
29
did not detect effects of hand use on
asymmetrical morphology in sensorimotor regions of
more than 465 normal adult brains. Although different
methodologies used in these studies could lead to oppo-
site conclusions, the analyses of anatomical asymmetries
associated with handedness in the primary sensory and
motor cortices are compelling.
Handedness and language ability are two of the most
obvious lateralized behaviours in humans. Taking note
of the convergence of functional and anatomical studies,
the asymmetrical cortical controls that regulate handed-
ness are tightly correlated with those for language ability.
But how are these controls established in humans?
Correlation of hand use and language ability
That most humans (more than 90%) prefer to use their
right hand has been observed in almost all cultures and
ethnicities throughout history
12,30
. Statistical studies sug-
gest that handedness might be under genetic control.
There are at least two well-known genetic models of
handedness
31,32
(BOX 1), and although these models seem
to reflect genetic mechanisms of cortical asymmetry
and handedness, genes that regulate these asymmetries
have not been identified. Furthermore, the question of
whether a single gene can control such complex processes
in the CNS is still unanswered
31
. Nevertheless, the single-
gene models proposed by Annett
33
and McManus
34
fit
statistical data of cerebral dominance for handedness
in humans. Identifying the gene(s) that regulates brain
asymmetry and handedness remains an appealing but
challenging task.
Why is there a left-hemisphere bias for handed-
ness and language ability? Preferred hand use has been
observed even at embryonic and fetal stages in humans,
long before language ability is developed. For example, in
most human embryos, the right hand is more developed
than the left at 7 weeks
35
. Using ultrasound, it has been
observed that at 15 weeks most fetuses prefer to suck their
right thumb, hinting that handedness is present prior
to birth
36
. Interestingly, Hepper et al.
37
followed up this
study of 75 individuals. They found that the 60 fetuses
that preferred to suck their right thumb were indeed
right-handed as teenagers, and of the 15 fetuses that
Figure 1 | Anatomical asymmetries in the human cerebral cortex. Coronal (a) and
horizontal (b) MRI of the Sylvian fissures (red arrows) in the human brain. The Sylvian
fissures separate the frontal lobes and temporal lobes in both hemispheres. The left (L)
fissure is more ventral (V) and extends further towards the posterior (P) than does the
right (R). Illustration of differences of sulcal depth between the left and right
hemispheres (c). Cortical regions that are deeper in the right hemisphere are shown in
red and yellow, whereas regions that are deeper in the left are shown in blue and green.
A, anterior; D, dorsal. Modified, with permission, from
REF. 11 © (2005) Elsevier Science.
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Magnetic source imaging
The detection of the changing
magnetic fields that are
associated with brain activity
and their subsequent
overlaying on magnetic
resonance images to identify
the precise source of the signal.
Paw preference
In a food-reaching task, paw
preference measures the
frequency of using either the
left or the right front paw to
reach food. It has been
observed in mice, rats, cats and
dogs.
preferred to suck their left thumb, 5 were right-handed
and 10 were left-handed. Moreover, several early studies
have shown that some cortical sulci and gyri, such as the
temporal gyri, are asymmetrical in human fetal brains
from 10–44 weeks
22,38,39
. Using the measurement of cer-
ebral blood flow, Chiron et al.
40
found that the maturation
of the right hemisphere precedes the left in the brains of
human infants between 1 and 3 years of age. This asym-
metrical pattern shifts towards the left hemisphere during
the process of development of language abilities at about
the age of 3
(REF.40). Additionally, Trevarthen
41
observed
that expressive gestures, such as communicative hand
movement, were asymmetrical in infants.
These results imply that anatomical and functional
brain asymmetry precedes uptake of information from
the environment and cognitive development. This in
turn suggests the existence of intrinsic controls that reg-
ulate brain asymmetries at early stages. Although these
kinds of study are interesting, one has to keep in mind
whether this early right-hand preference is controlled by
high-level regulation in the left hemisphere of the cortex,
or by spontaneous movement regulation in the spinal
cord. Furthermore, whether early brain asymmetries
contribute more to handedness or to language ability still
remains an intriguing and challenging question
12
.
Because anatomical asymmetries of certain areas in
the human brain are associated with language ability,
several researchers have made efforts to map asym-
metries of the planum temporale and Broca’s area in the
brains of chimpanzees and great apes
42–44
. They found
that simian brains also have asymmetries, which resem-
ble those of humans. These studies suggest that brain
structures associated with language ability might have
existed before humans evolved. However, it is not clear
whether vocal communication is asymmetrical in non-
human primate brains or how these asymmetrical struc-
tures are involved in vocal processing
45
. Furthermore,
because of the complex structure of the cerebral cortex,
the mapping of areas that correspond in human and
primate brains is difficult
46
.
Which hemispheric asymmetry (for handedness
or for language ability) appeared first in evolution still
remains a puzzle. Further comparative studies of brain
asymmetry and handedness in non-human primates will
help us to understand the relationship between handed-
ness and language ability in humans
47
.
Evolutionary mechanisms of biased hand use
More than 90% of the human population is right-handed,
and biased hand use is also observed in non-human
primates and other mammals. But whether there is a
dominant preference for one hand at a population level
is still debatable. What has made most humans right-
handed during evolution is still unknown.
Handedness in non-human primates. There are many
contradictory reports about hand use in non-human
primates, such as chimpanzees. A broad range of
manual tasks have been observed in chimpanzees,
including simple reaching, bimanual feeding, coordi-
nated bimanual actions, throwing, manual gestures and
so on
48,49
. Although these observations have led to the
argument that, for some measures, chimpanzees are
right-handed, most of these findings are from captive
great apes; evidence of population-level handedness in
wild apes is extremely sparse
48,49
. Therefore, these stud-
ies do not conclude that there is a dominant preference
for hand use in non-human primates at the population
level.
A recent report of hand preferences during termite-
fishing/probing actions of chimpanzees is interesting.
First, Lonsdorf and Hopkins
50
studied wild chimpanzees
living in the Gombe National Park, Tanzania, but not
captive chimpanzees. Second, they observed termite-
fishing actions, which require fine motor skill. They
claimed that directional biases in hand use vary depend-
ing on the type of tool use. Therefore, the question of
whether there is strong handedness in non-human
primates might be confounded by biases in the types
of motor skill required. Tests that better discriminate
behavioural biases in wild primates are needed before
any definitive conclusions can be drawn.
Paw preference in other mammals. A well-studied
lateralized manual behaviour of many mammals is the
food-reaching task, defined by
paw preference. Although
paw preference has been observed and studied in mice,
rats, cats and dogs, it does not seem biased to either the
left or the right front paw at a population level
51–56
. For
example, paw preference was observed among domestic
cats, but no significant bias in preference was found at
the level of the group
53
. In mice, although there is paw
preference in each individual mouse, approximately half
of the mice studied preferred to use the left paw and half
preferred to use the right
57,58
. There are also differences
in the strength and direction of paw preference between
mouse strains, indicating that genetic background is an
important influence on this behaviour
55
.
Paw preference in mice has encouraged scientists
to find the genetic causes of this manual lateralization.
Collins
59
attempted to breed left- or right-handed mice,
and although he was unable, by inbreeding, to create a
mouse strain that prefers to use only the left or the right
front paw, he did succeed in generating mice that show
a strong lateralization. For example, the HI strain was
bred using mice that showed consistent right or left paw
use in a food-reaching task, and the LO strain was bred
using mice with little overall paw preference
59
.
Box 1 | Genetic models of human handedness
Marian Annett
33
has proposed that the inheritance of the right-shift (RS) gene shifts the
manual skills in favour of the right hand instead of the left. She emphasizes that RS
influences left cerebral dominance rather than handedness; the effect of RS is to impair
the control of speech systems in the right hemisphere, allowing language abilities to
function in the left side. Handedness is just the secondary consequence of the left-
cerebral cortical dominance
93
.
The other model was proposed by Chris McManus
34
. He suggests that handedness is
controlled by two alleles: D (dextral) and C (chance). According to his model, the
homozygous DD genotype produces only right-handers, whereas the homozygous CC
genotype produces a random mixture of 50% right-handers and 50% left-handers.
Furthermore, the heterozygote, DC, produces 25% left-handers and 75% right-handers.
This model reflects the Mendelian model of genotype and phenotype distribution.
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Is paw preference associated with lateralized brain
anatomy and/or function in mice? The direction of paw
preference seems to correlate with the dominance of
dopamine expression levels in the brain: a mouse that
prefers to use the left front paw has a higher dopamine
level in the left hemisphere than in the right, although
the physiological implications of this correlation are
unknown
60,61
. Selectively bred mice (the O/AP strain)
with supernumerary whiskers on the right side of the
face and corresponding supernumerary barrels in the left
barrel field showed a higher preference for using the left
front paw. Likewise, mice with supernumerary whiskers
on the left side of the face preferred to use the right front
paw
62
. This biased front-paw use might be the result of
competition for cortical representation between the size
of the motor cortex and the somatosensory barrel field in
which the whiskers are represented. A larger S1 (the bar-
rel field) in the left hemisphere, for example, might make
the size of the left motor cortex smaller, and lead to biased
left front-paw use controlled by the right hemisphere.
Moreover, the areas of whisker-pad representation in
the S1 between the left and right hemispheres of adult rats
have shown striking variations (that is, asymmetries) in
individuals. However, these asymmetries are not biased
to either the left or the right hemispheres
63,64
. Does the
asymmetry of the S1 provide a hint that paw preference
has corresponding and asymmetrical cortical structures
that control it? It will be interesting to map the sizes of the
S1 regions and the direction of paw preference in mice.
In terms of the distribution of hand use, there is a
consistent 9:1 ratio of right/left hand preference reported
in humans, higher than has been reported for any other
mammal
12,50
. The directional manual task in mice, like
paw preference, might be regulated by the formation of
stable neural circuits, but it has a random distribution at
the population level. Given these examples of low or no
bias in chimpanzees and mice, it is an intriguing puzzle
as to how consistent right-hand dominance evolved in
humans. Corballis
31
has proposed that there was a genetic
mutation in hominid evolution that promoted preferen-
tial use of the right hand and is now seen in modern
humans. This evolutionary bias might be advantageous
as it could increase brain capacity and social cohesion
65
.
Applying genomic approaches, particularly the complete
sequencing of the human and chimpanzee genomes,
will provide a considerable insight into the evolution-
ary mechanisms of lateralized human behaviours and
human brain development and asymmetry
47,66–69
.
Body and brain asymmetries
Little is known about the genetic causes of brain ana-
tomical and functional asymmetries
70
. By contrast, stud-
ies of molecular regulation of asymmetries in the visceral
organs, such as the heart and lungs, have made encour-
aging progress
(BOX 2). Inspired by the identification
of molecules that have essential roles in visceral organ
asymmetry, researchers have succeeded in identifying
molecules that regulate brain asymmetry in zebrafish,
perhaps the only species that has been well studied
with respect to brain asymmetry
(BOX 3). Conserved
molecules that regulate body asymmetry, such as
Nodal
and ion channel related gene products, are also essential
for regulating asymmetry of the epithalamus, a small
structure of the diencephalons
71,72
.
Do the same molecular mechanisms that regulate
body asymmetry also cause human brain asymmetry?
The complete reversal of normal organ position, such as
heart and lungs, is called situs inversus. With the excep-
tion of the reversed frontal and occipital petalia observed
using anatomical and functional MRI techniques, the
left-hemisphere dominance for language was still found
to be similar in individuals with situs inversus and in
normal subjects
73
. Nor did lateralization of auditory
processing show any differences between individuals
with situs inversus and normal subjects
74
. Moreover,
50% of individuals with
Kartagener’s syndrome, a dis-
order caused by cilia with a decreased or total absence
of motility, have been found to have situs inversus
75
. This
disorder might confirm the function of cilia in regulat-
ing visceral organ asymmetry, as defects in cilia mobility
might result in the random distribution of NODAL mol-
ecules
(BOX 2). However, the situs inversus patients with
Kartagener’s syndrome developed normal handedness
76
.
Therefore, it seems reasonable that the molecules and
mechanisms that regulate visceral organ asymmetries
might be distinct from those that regulate brain asym-
metries and handedness
70,77
.
Box 2 | Molecular regulation of visceral organ asymmetry
Several studies have elegantly addressed the molecular regulation of the left–right
asymmetry of internal organs, such as the heart, stomach, lungs and intestines of
vertebrate bodies
94,95
. Three signalling pathways (SHH, FGF8 and NODAL) have crucial
roles in left–right body determination
96,97
. In the chick embryo, sonic hedgehog (SHH) and
its target gene caronte (CAR ) are expressed to the left of the chick node (a structure of
the body organizer in chicks) , whereas FGF8 is expressed to the right of the chick node
98–
100
. Misexpression of SHH on the right side of the node is sufficient to induce heart
formation on the right
98
. In the mouse embryo, neither SHH nor FGF8 is expressed
asymmetrically
97
. Instead, the unidirectional rotation of monocilia on the surface of the
mouse node directs the NODAL molecule to the left and activates its downstream genes,
such as Lefty2 and Pitx
101–103
. Moreover, early differential ion flux, such as that driven by
the H
+
and K
+
ATPase transporter, was shown to cause early body asymmetry
104
. The
neurotransmitter serotonin was recently reported upstream of asymmetrically expressed
genes (such as SHH) in chick and frog embryos, and has a role in early patterning of the
left–right body axis
105,106
.
Box 3 | Molecular regulation of zebrafish brain asymmetry
The asymmetries of the epithalamus, which are exemplified by the habenula and the
pineal complex, are well studied in zebrafish
71
. Although the functional consequences of
epithalamus asymmetry are still unclear, it seems to be involved in regulating sexual
activities, photoreception and communication
71,107
. Both the habenula and the pineal
complex show asymmetries on the left side in zebrafish. Interestingly, genes involved in
the Nodal pathway, such as the Nodal-related gene cyclops and Nodal downstream
genes lefty1 and pitx2, were shown to control the laterality of the asymmetry, suggesting
that a conserved signalling pathway that regulates visceral laterality also underlies an
anatomical asymmetry of the zebrafish brain
72,108–110
. Moreover, a recent report has shown
that the frequent situs inversus (fsi) line of zebrafish displayed concordant reversal of
visceral organ and neuroanatomical asymmetries in the diencephalons
111
. Interestingly,
fsi zebrafish also showed a reversal of some behavioural responses, which has not been
detected in mammals with situs inversus
111
. These results indicate that the molecular
regulation of brain and body asymmetries can be species specific.
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RABL2B
SUFU
SH3GL2
NEUROD6
NEDD4
TMSB4X
MAGOH
HEY1
LAMR1
IGF1
IFIT4
ID2
DAPPER1
CUTL1
BICD2
BAIAP2
ATP2B3
Le
IGFBP5
MYT1L
MEF2C
MATR3
P311
STMN4
LMO4
BAI1
AUTS2
ARHA
Right
8 76543210
0 0.5 1 1.5 2 2.5 3
Relative gene expression levels
abc
Epidermal ectoderm
Roof plate
Floor plate
Notochord
Neural
tube
Anterior
neural ridge
Brain cortical
hemispheres
Serial analysis of gene
expression
(SAGE). A method for
comprehensive analysis of
gene expression levels and
patterns using PCR
amplification and generating
SAGE libraries.
Our recent studies, using a genomic screening
approach, further support this idea. Using a
serial analysis
of gene expression
(SAGE) technique, we measured gene
expression levels in the left and right hemispheres of
human fetal brains
78
. We verified 27 genes that are dif-
ferentially expressed in the hemispheres of 12-week-old
human fetal brains by using either real-time reverse
transcription (RT)-PCR or in situ hybridization
(FIG. 2).
Most genes identified using SAGE analyses function in
signal transduction and gene expression regulation
47
.
Among them, the transcription factor Lim domain only 4
(
LMO4) showed consistent asymmetry of expression in
human fetal brains at 12 weeks and 14 weeks, and less so
at 16 and 17 weeks
78
. However, we did not detect genes
that have essential roles in visceral organ asymmetry,
such as genes involved in the sonic hedgehog (
SHH)
or NODAL pathways, which are also differentially
expressed in human fetal brains
78
. Because the earliest
stage analysed was in the human fetus at 12 weeks, it
cannot be ruled out that molecules regulating body
asymmetry might also be differentially expressed in
human embryonic brains (for example, at 8–10 weeks).
It will be interesting to measure gene expression levels
in the left and right hemispheres in human embryonic
brains (8–10 weeks) using SAGE or cDNA microarray
approaches.
Molecular regulation of brain asymmetry
An essential step leading towards asymmetry is to break
symmetry
79
. Although the initiation mechanisms of
breaking symmetry are still unknown, an uneven dis-
tribution of molecules that are essential for left–right
body axis patterning could be important for this bio-
logical event.
How, then, is symmetry broken in the CNS?
Neuroepithelial cells divide vigorously, fold dorsally and
form a neural groove during early embryonic develop-
ment
80
. The neural groove continues to grow, and the
dorsal parts meet at the midline and fuse to form a neural
tube
80
. Neural tube development is accompanied by the
formation of the
notochord and the induction of the floor
plate
81
. Numerous studies have shown that the notochord
is a patterning centre for the ventral neural tube
82
. In the
forebrain, a structure anterior to the notochord is called
the prechordal plate
83
. Molecules secreted from the noto-
chord, such as SHH, function as
morphogens to induce
and maintain the ventral property and neural cell types
in the spinal cord
82
. Similar morphogens also induce
and pattern the forebrain, and are probably secreted
from the notochord or the prechordal plate
84
. Moreover,
the patterning centres are not limited to the notochord
and the ventral neural tube. Morphogens, such as bone
morphogenetic proteins and WNTs, are secreted from
the roof plate in the neural tube
85
.
One possible mechanism for breaking symmetry
in the brain is that the morphogens secreted from the
ventral (floor plate or prechordal plate) and/or dorsal
(roof plate) midlines are distributed differently between
the left and right (
FIG. 3a,b). The different expression
levels of morphogens induce differential expression
of downstream transcription factors, such as LMO4
(REF. 78), and eventually lead to brain asymmetry.
Recent studies of the molecular regulation of corti-
cal regionalization have identified a patterning centre
in the anterior cortex
2–4
. An important molecule that is
secreted from the anterior cortical region is fibroblast
growth factor 8 (
FGF8)
86
. The ectopic expression of
FGF8 can expand the motor cortex and shift the func-
tional regions of the cortex caudally
86
. It is possible that
the expression levels of morphogens secreted from the
anterior cortical region might be different in the left and
right hemispheres
(FIG. 3c). The asymmetrical expression
Figure 2 | Asymmetrically expressed genes in 12-week-old human fetal brains,
detected by serial analysis of gene expression and real-time reverse
transcription (RT)-PCR. The cDNA made from the perisylvian regions of the left and
right hemispheres of two 12-week-old human fetal cortices were used as templates for
real-time RT-PCR. The relative gene expression levels are average ratios of gene
expression detected by RT-PCR between the left and right hemispheres of two brains.
These differential gene expression levels also match those measured by serial analysis of
gene expression (SAGE)
78
. 27 genes showing consistent differential expression are listed.
Among them, 17 genes were highly expressed in the left perisylvian regions, whereas 10
genes were highly expressed in the right.
Figure 3 | Three models of molecular induction of brain asymmetry. a | Whereas the
neural tube (red) is derived from the ectoderm, the notochord (blue) is derived from the
mesoderm and accompanies the neural tube formation. During neural tube
development, the most dorsal part of the neural tube becomes the roof plate (green),
whereas the most ventral part of the neural tube becomes the floor plate (blue). The
forebrain is developed from the most rostral region in the neural tube. In the forebrain,
the morphogens secreted from the notochord or the prechordal plate (not shown) might
be differentially distributed between the left and right neural tube. b | Similarly, uneven
secretion of molecules might also occur in the roof plate. Different morphogen
expression levels in the left and right neural tube might break the symmetry of brain
patterning and induce asymmetrical expression of downstream genes. c | Anterior
signals might also induce cortical asymmetry. The patterning centre in the most rostral
neural tube — for example, the anterior neural ridge (green) — could be a source for
cortical asymmetrical patterning. The distribution of molecules secreted from this area
might be different in the left and right hemispheres.
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© 2006 Nature Publishing Group
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© 2006 Nature Publishing Group
RLR L
Notochord
A structure composed of cells
derived from the mesoderm
and defines the primitive axis
of the embryo. It lies between
the neural tube (spinal cord)
and the gut.
Morphogen
A diffusible substance that
carries information influencing
the movement and
organization of cells during
morphogenesis. It normally
forms a concentration gradient.
of regional markers, such as LMO4, could reflect asym-
metrical topographic mapping of functional regions
along the anterior–posterior axis in the cortex
78
.
Future work will include the identification of more of
the morphogens that pattern the early cortex and their
downstream targets. Consistent with regionalization
in the cortex, which involves complex gene expression
and regulation
4
, brain asymmetry and handedness are a
conjugated result of molecular regulation, neural con-
nections and plasticity.
Conclusions and future perspectives
The challenge of studying brain asymmetry is that
because the obvious anatomical and functional asym-
metries have been identified largely in humans, we can-
not carry out direct experiments. The recent behavioural
studies in non-human primates, such as the investigation
of handedness in chimpanzees, might help us to better
understand how human handedness has evolved
50
. In
particular, the comparison of human and chimpanzee
genomes has enriched our knowledge of the evolution-
ary mechanisms of human brain development
47,66–69
.
Similar studies might help us to understand the evolu-
tionary regulation of human brain asymmetry.
Several human neurological disorders show dis-
rupted normal brain asymmetry. For example, reduced
and reversed anatomical brain asymmetry has been
reported in individuals with schizophrenia, autism or
dyslexia
87–90
, suggesting a potential indirect relationship
between the causes of these disorders and the asym-
metrical development of the human cerebral cortex.
Recently, several studies have reported clinical cases of
polymicrogyria — a malformation of cortical develop-
ment that is characterized by many small gyri in the
cortex — that occurs only on one side of the cortex;
this is known as unilateral polymicrogyria
91,92
(FIG. 4).
Patients have seizures, motor dysfunction and mental
retardation. A genetic cause of unilateral right-sided
polymicrogyria is suggested by the existence of several
pedigrees in which the disorder is present in more than
one individual of an affected family
92
. These studies
indicate that unilateral polymicrogyria can be inherited
as a Mendelian trait, suggesting that there might be a
gene that is required for the development of the right
perisylvian region
92
. Using forward genetic approaches
to map genes that cause disrupted brain asymmetry
might reveal their normal function in asymmetrical
development of the brain.
Faster development and improvement of large-scale
screening approaches at the genomic level could make
the identification of asymmetrically expressed genes in
human and mouse brains easier and quicker. Generating
genetically engineered mice can help us to understand
the functions of these genes in brain development. Using
these mouse models can also help to reveal the neural
circuitries that regulate brain asymmetry and lateral-
ized behaviours. However, unlike visceral organ asym-
metries, which are easy to detect, brain asymmetry relies
largely on fine brain mapping and reliable behavioural
tests. Therefore, the development of molecular imaging
techniques and an improved understanding of lateral-
ized behaviours in rodents will be extremely useful for
studies of brain asymmetry.
Figure 4 | Unilateral polymicrogyria detected using MRI. Polymicrogyria (indicated
by arrows) is detectable in the right hemispheres in both brains shown. An apparent
increase in cortical thickness is observed in the right (R) hemispheres, whereas the
cortices of the left (L) hemispheres appear entirely normal. Modified, with permission,
from
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Acknowledgements
Owing to space limitations, we apologize for being unable to
cite many excellent papers in this field. We thank the referees
for critical reading and useful comments, and B. Chang for the
MRI images in figure 4. The authors were supported by grants
from the National Institute of Neurological Disorders and
Stroke, National Institutes of Health. C.A.W. is an investigator
of the Howard Hughes Medical Institute.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CAR | FGF8 | LMO4 | Nodal | SHH
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Kartagener’s syndrome
FURTHER INFORMATION
Sun’s homepage: http://www.med.cornell.edu/research/
taosun/index.html
Access to this links box is available online.
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