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No differences in the number of striatal projection neurons or interneurons between Robo1 / and Robo1 / adult mice. Immunostaining of coronal brain sections from adult Robo1 / and Robo1 / mice for the striatal projection neuron markers CB (A, B) and DARP-32 (D, E), and for the interneuron markers PV (G, H), SST (J, K), and ChAT (M, N). The quantitation of immunopositive neurons for each marker is shown adjacent to the sections (C, F, I, L, O). Scale bar, 100 m. Abbreviations: Str, Striatum; WM, white matter. Error bars indicate SEM.
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Cortical interneurons, generated predominantly in the medial ganglionic eminence, migrate around and avoid the developing striatum in the subpallium en route to the cortex. This is attributable to the chemorepulsive cues of class 3 semaphorins expressed in the striatal mantle and acting through neuropilin (Nrp1 and Nrp2) receptors expressed in thes...
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Context 1
... also analyzed sections taken from adult (3 months) Robo1 / (n 3) and Robo1 / (n 3) mice and immuno- stained for CB and DARPP-32 (markers of 85 and 98% of mature striatal projection neurons, respec- tively) (Ouimet et al., 1998). This analysis showed no differences in the number of CB (Fig. 3A-C) or DARPP-32 cells (Fig. 3D-F ) at any level of the adult striatum of Robo1 / mice com- pared with Robo1 / littermates. We then assessed whether the number of mature striatal interneurons was changed in mice lacking Robo1 receptor by immunostaining sections of adult Robo1 / (n 3) and Robo1 / (n 3) mice for three mark- ers of ...
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... also analyzed sections taken from adult (3 months) Robo1 / (n 3) and Robo1 / (n 3) mice and immuno- stained for CB and DARPP-32 (markers of 85 and 98% of mature striatal projection neurons, respec- tively) (Ouimet et al., 1998). This analysis showed no differences in the number of CB (Fig. 3A-C) or DARPP-32 cells (Fig. 3D-F ) at any level of the adult striatum of Robo1 / mice com- pared with Robo1 / littermates. We then assessed whether the number of mature striatal interneurons was changed in mice lacking Robo1 receptor by immunostaining sections of adult Robo1 / (n 3) and Robo1 / (n 3) mice for three mark- ers of nonoverlapping subpopulations of ...
Context 3
... by immunostaining sections of adult Robo1 / (n 3) and Robo1 / (n 3) mice for three mark- ers of nonoverlapping subpopulations of striatal interneu- rons, PV, SST, and ChAT ( Kawaguchi et al., 1995). Counts of the three cell types also showed no differences between the two groups of animals throughout the rostral-caudal extent of the striatum (Fig. 3G-O). Together, our analysis of developing and adult animals suggests that deletion of Robo1 receptor does not impair the establishment of striatal projection neu- rons or ...
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Citations
... Immunofluorescence, immunohistochemistry, and tissue processing were performed as previously described (76). In short, embryonic (E11.5, E12.5, E14.5, and E19) and postnatal brains (P0 and P56) were fixed in 4% paraformaldehyde, made in phosphate-buffered saline (PBS), for 4 hours at 4°C. ...
Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO 2 . The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.
... DPSC and SHED constitute key components of the dental pulp microenvironment and have been recognized for their ability to differentiate into multiple cell types, including those contributing to dental pulp and dentin regeneration [40][41][42]. The expression of SEMA4D within these cells could suggest that this protein may influence their proliferative or migratory abilities [30,43,44]. Interestingly, our fluorescence staining revealed that SEMA4D expression is associated with vascular endothelial cells within dental pulp tissues. ...
This work aimed to evaluate the effect of Semaphorin 4D (SEMA4D) signaling through Plexin B1 on the vasculogenic differentiation of dental pulp stem cells. We assessed the protein expression of SEMA4D and Plexin B1 in dental pulp stem cells (DPSC) from permanent human teeth and stem cells from human exfoliated deciduous (SHED) teeth using Western blots. Their expression in human dental pulp tissues and DPSC-engineered dental pulps was determined using immunofluorescence. We then exposed dental pulp stem cells to recombinant human SEMA4D (rhSEMA4D), evaluated the expression of endothelial cell differentiation markers, and assessed the vasculogenic potential of rhSEMA4D using an in vitro sprouting assay. Lastly, Plexin B1 was silenced to ascertain its role in SEMA4D-mediated vasculogenic differentiation. We found that SEMA4D and Plexin B1 are expressed in DPSC, SHED, and human dental pulp tissues. rhSEMA4D (25–100 ng/mL) induced the expression of endothelial markers, i.e., vascular endothelial growth factor receptor (VEGFR)-2, cluster of differentiation (CD)-31, and tyrosine kinase with immunoglobulin-like and EGF-like domains (Tie)-2, in dental pulp stem cells and promoted capillary-like sprouting in vitro (p < 0.05). Furthermore, Plexin B1 silencing abrogated the vasculogenic differentiation of dental pulp stem cells and significantly inhibited capillary sprouting upon exposure to rhSEMA4D. Collectively, these data provide evidence that SEMA4D induces vasculogenic differentiation of dental pulp stem cells through Plexin B1 signaling.
... During their migration from the subpallium and while attracted to the cortex by several diffusible molecules, interneurons avoid transiting through the POA and the striatum, immediately adjacent to the Ganglionic eminences. This is due to the action of chemorepulsive cues secreted by the POA and striatum (Marín et al., 2003;Nóbrega-Pereira et al., 2008;Hernández-Miranda et al., 2011). In vitro experiments have shown that diverse molecules mediate this chemorepulsive effect. ...
... Striatum and POA express semaphorins Sema3A and Sema3B, which can be sensed by Robo1 receptor expressed by cortical INs. The interaction between ephrinA and their receptors also participates Nóbrega-Pereira et al., 2008;Hernández-Miranda et al., 2011). ...
The mammalian cerebral cortex represents one of the most recent and astonishing inventions of nature, responsible of a large diversity of functions that range from sensory processing to high-order cognitive abilities, such as logical reasoning or language. Decades of dedicated study have contributed to our current understanding of this structure, both at structural and functional levels. A key feature of the neocortex is its outstanding richness in cell diversity, composed by multiple types of long-range projecting neurons and locally connecting interneurons. In this review, we will describe the great diversity of interneurons that constitute local neocortical circuits and summarize the mechanisms underlying their development and their assembly into functional networks.
... It is increasingly clear that semaphorins in uence various cellular processes in the development of the nervous system, from neuronal migration [22] and axonal trimming [23,24] to synapse formation and function [25]. Many effects are dependent on their ability to act as repulsive or attractive proteins that can control the cytoskeleton [26,27]. ...
Background
Glioblastoma (GBM) is the most invasive and common form among brain cancers in adults. GBM is characterized for its poor survival and markedly high tumors heterogeneity with shortage of effective therapies. Semaphorins, a family of membrane-associated and secreted proteins, were originally defined as neuronal growth pyramidal proteins involved in directing repulsive axons. Semaphorins are repeatedly involved in the evolution of neural circuits, involving not only the generation and guidance of neurons, but also the recognition of target regions and cells and synapse formation. However, the differential expression and clinical prognostic value of semaphorins in GBM were not yet available clarity.
Methods
In this study, various databases including ONCOMINE (1159 samples), GEPIA (TCGA and GTEx dataset), UALCAN (samples from TCGA dataset), cBioPortal (604 samples from GDAC firehose of TCGA dataset), GeneMANIA(data from publicly available daatbases, e.g. GEO, BioGRID) and TIMER(samples from TCGA) were exploited.
Results
We found that in GBM tissues the transcriptional levels of SEMA3A/3B/3E/3F/5A/6A were markedly elevated, while those of SEMA3G/4A/4D/4F/5B were markedly reduced. GBM patients with lower levels of SEMA3F/4F transcription had a significantly better outcome. The function of semaphorins was mainly related to the regulation of cell growth and development. Besides, we found that the expression of semaphorin was significantly correlated with the infiltration of immune cells.
Conclusions
Semaphroins are differentially expressed in glioblastoma compared with normal brain tissue. They could provide diverse prognostic values, participate in various molecular pathways. In addition, the semaphorin protein family plays an important role in immune cell infiltration. Our study may supply potential target genes for the treatment of glioblastoma while providing new insights into the selection of prognostic biomarkers. Besides, our results may offer new insights into immunotherapy targeting and analysis of protein co-expression in SEMA for glioblastoma.
... The Roundabout (Robo) family of receptors together with their ligands, the Slit proteins, are abundantly expressed in the developing forebrain and play critical roles in the generation and migration of cortical interneurons (Andrews et al., 2006;Hernandez-Miranda et al., 2011) and also pyramidal neurons (Yeh et al., 2014). It has also been shown that Robo1 and Robo 4 play a role in radial migration of pyramidal neurons (Zheng et al., 2012;Gonda et al., 2013). ...
The remarkable sensory, motor, and cognitive abilities of mammals mainly depend on the neocortex. Thus, the emergence of the six-layered neocortex in reptilian ancestors of mammals constitutes a fundamental evolutionary landmark. The mammalian cortex is a columnar epithelium of densely packed cells organized in layers where neurons are generated mainly in the subventricular zone in successive waves throughout development. Newborn cells move away from their site of neurogenesis through radial or tangential migration to reach their specific destination closer to the pial surface of the same or different cortical area. Interestingly, the genetic programs underlying neocortical development diversified in different mammalian lineages. In this work, I will review several recent studies that characterized how distinct transcriptional programs relate to the development and functional organization of the neocortex across diverse mammalian lineages. In some primates such as the anthropoids, the neocortex became extremely large, especially in humans where it comprises around 80% of the brain. It has been hypothesized that the massive expansion of the cortical surface and elaboration of its connections in the human lineage, has enabled our unique cognitive capacities including abstract thinking, long-term planning, verbal language and elaborated tool making capabilities. I will also analyze the lineage-specific genetic changes that could have led to the modification of key neurodevelopmental events, including regulation of cell number, neuronal migration, and differentiation into specific phenotypes, in order to shed light on the evolutionary mechanisms underlying the diversity of mammalian brains including the human brain.
... Functional integration of INs in cortical circuits depends on their proper laminar positioning and their ability to connect to appropriate local cellular partners (Fishell and Kepecs, 2020;Lim et al., 2018a). To reach the cortex, INs first leave the subpallium (Herná ndez-Miranda et al., 2011;van den Berghe et al., 2013;Flames et al., 2004;Nó brega-Pereira et al., 2008;Raki c et al., 2015) and migrate tangentially within migratory streams located in the subventricular zone (SVZ) and marginal zone (MZ) (Lavdas et al., 1999;Lim et al., 2018b;Martini et al., 2009;Tanaka et al., 2009;Tiveron et al., 2006). Then, they exit tangential streams to distribute in the nascent cortex and are driven toward specific layers where they connect with preferential targets (Bartolini et al., 2017;Miyoshi and Fishell, 2011;Sá nchez-Alcañ iz et al., 2011;Ló pez-Bendito et al., 2008). ...
In the mammalian cerebral cortex, the developmental events governing allocation of different classes of inhibitory interneurons (INs) to distinct cortical layers are poorly understood. Here we report that the guidance receptor PlexinA4 (PLXNA4) is upregulated in serotonin receptor 3a-expressing (HTR3A⁺) cortical INs (hINs) as they invade the cortical plate, and that it regulates their laminar allocation to superficial cortical layers. We find that the PLXNA4 ligand Semaphorin3A (SEMA3A) acts as a chemorepulsive factor on hINs migrating into the nascent cortex and demonstrate that SEMA3A specifically controls their laminar positioning through PLXNA4. We identify deep-layer INs as a major source of SEMA3A in the developing cortex and demonstrate that targeted genetic deletion of Sema3a in these INs specifically affects laminar allocation of hINs. These data show that, in the neocortex, deep-layer INs control laminar allocation of hINs into superficial layers.
... Whereas the role of Slit-Robo signaling in axon guidance is conserved from Drosophila to mammals (Bagri et al., 2002;Andrews et al., 2006;Fouquet et al., 2007;López-Bendito et al., 2007;Unni et al., 2012), several additional roles of Slit-Robo signaling have been identified in mammals. Studies have shown that Robomediated signaling is required for the proliferation of neural progenitor cells, as well as for the migration and morphological differentiation of cortical neurons (Andrews et al., 2006(Andrews et al., , 2008Barber et al., 2009;Hernández-Miranda et al., 2011;Zheng et al., 2012;Borrell et al., 2012;Gonda et al., 2013;Yeh et al., 2014;Cárdenas et al., 2018;Blockus et al., 2019). These findings support the view that Robo signaling plays important roles in addition to axonal pathfinding in the developing neocortex. ...
The formation of the neocortex relies on intracellular and extracellular signaling molecules that are involved in the sequential steps of corticogenesis, ranging from the proliferation and differentiation of neural progenitor cells to the migration and dendrite formation of neocortical neurons. Abnormalities in these steps lead to disruption of the cortical structure and circuit, and underly various neurodevelopmental diseases, including dyslexia and autism spectrum disorder (ASD). In this review, we focus on the axon guidance signaling Slit-Robo, and address the multifaceted roles of Slit-Robo signaling in neocortical development. Recent studies have clarified the roles of Slit-Robo signaling not only in axon guidance but also in progenitor cell proliferation and migration, and the maturation of neocortical neurons. We further discuss the etiology of neurodevelopmental diseases, which are caused by defects in Slit-Robo signaling during neocortical formation.
... Furthermore, our findings are consistent with recent evidence showing that ROBO1 affects the development of the central nervous system during the embryonic and fetal stages [107,108], and of the sensory pathways involved in the reading acquisition process [108]. ROBO1 encodes a receptor protein for the SLIT family of proteins, and plays an essential role in axon guidance (e.g., midline crossing and neuronal migration of precursor cells) [107,[109][110][111][112][113][114][115], as demonstrated by both RNAi and knockout experiments in mice and rats [107,[116][117][118][119][120]. Thus, the present study builds upon these past works by corroborating indirect pathways linking variants spanning ROBO1 with reading (dis)ability via ROBO1 s effects upon rapid auditory and visual motion processing. ...
Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from ROBO1-rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that ROBO1 is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior.
... The reported link between ROBO1 and grey matter volume is supported by a large body of molecular genetic literature suggesting that this gene plays a crucial role for prenatal growth of the rodent neocortex. Specifically, there is converging evidence that ROBO1 regulates neuronal migration (i.e., the positioning of neurons in cortical layers during intrauterine brain maturation) [13,16,17]. Moreover, ROBO1 might also contribute to the proliferation of neurons in the cortex [18]. ...
Mathematical ability is heritable and related to several genes expressing proteins in the brain. It is unknown, however, which intermediate neural phenotypes could explain how these genes relate to mathematical ability. Here, we examined genetic effects on cerebral cortical volume of 3-6-year-old children without mathematical training to predict mathematical ability in school at 7-9 years of age. To this end, we followed an exploration sample (n = 101) and an independent replication sample (n = 77). We found that ROBO1, a gene known to regulate prenatal growth of cerebral cortical layers, is associated with the volume of the right parietal cortex, a key region for quantity representation. Individual volume differences in this region predicted up to a fifth of the behavioral variance in mathematical ability. Our findings indicate that a fundamental genetic component of the quantity processing system is rooted in the early development of the parietal cortex.
... Several studies point out the importance of the Slit/Robo repulsive signals in neuronal migration (Wu et al., 1999;Causeret et al., 2002;Andrews et al., 2006;Di Meglio et al., 2008). In the developing forebrain, through semaphorin-neuropilin/plexin signaling modulation, Robo1 guides interneuron migration through the subpallium and into the cortex (Hernández-Miranda et al., 2011). Oppositely to Robo1 and Robo2 receptors, Robo3 does not bind Slits but instead interacts with Dcc and Netrin-1. ...
Spinal dorsal interneurons, which are generated during embryonic development, relay and process sensory inputs from the periphery to the central nervous system. Proper integration of these cells into neuronal circuitry depends on their correct positioning within the spinal parenchyma. Molecular cues that control neuronal migration have been extensively characterized but the genetic programs that regulate their production remain poorly investigated. Onecut (OC) transcription factors have been shown to control the migration of the dorsal interneurons (dINs) during spinal cord development. Here, we report that the OC factors moderate the expression of Pou2f2, a transcription factor essential for B-cell differentiation, in spinal dINs. Overexpression or inactivation of Pou2f2 leads to alterations in the differentiation of dI2, dI3 and Phox2a-positive dI5 populations and to defects in the distribution of dI2-dI6 interneurons. Thus, an OC-Pou2f2 genetic cascade regulates adequate diversification and distribution of dINs during embryonic development.
