Figure 4 - available via license: Creative Commons Attribution 2.5 Generic
Content may be subject to copyright.
Expression of cell signalling genes in the interneuron migratory streams in the developing forebrain as seen by in situ hybridization at E13.5 and E15.5. A higher-magnification image of the cortex is shown beside each low-magnification panel of the forebrain. The upper panels show the expression of receptor genes in the PPL at E13.5 and in the MZ at E15.5. The lower panels show the expression of receptor genes predominantly in the IZ at E13.5 and E15.5. (A–B′) The expression of Reelin was used as an internal control, as it is known that it is expressed exclusively in cells (presumptive CR cells) in the PPL at E13.5 and in the MZ at E15.5. (C–D′) Expression of Dab1 is observed only within the PPL at E13.5 and in the MZ and SP (after the splitting of the CP) at E15.5. (E–F′) The interneuron marker Lhx6 was also used as an internal control, as it is known to be expressed in both the PPL and IZ at E13.5 (E–E′), and more widely, but predominantly in the MZ and IZ/SVZ, at E15.5 (F–F′). (G–L′) Expression of the cell signalling genes Cdc42ep3 (G–H′), Plcb1 (I–J′) and Rasgef1b (K–L′) was observed predominantly within the IZ at E13.5, and within the IZ/SVZ at E15.5. Scale bar in A–B′: 200 μm.
Source publication
Cortical interneurons originate in the ganglionic eminences of the subpallium and migrate into the cortex in well-defined tangential streams. At the start of corticogenesis, two streams of migrating neurons are evident: a superficial one at the level of the preplate (PPL), and a deeper one at the level of the intermediate zone (IZ). Currently, litt...
Citations
... Cell-to-cell contacts modulate this complex intercommunication through a gradient of different molecules called morphogens. Morphogens are secreted during the proliferation of neural progenitor cells and determine the programmed movement and distribution of neural and glial progenies resulting from the proliferation, distribution, and migration of these cell lineages during the formation of the cerebral cortex, cerebellum, and spinal cord [38,39]. Several lipidrelated molecules, such as sphingolipids, glycolipids, phospholipids, thromboxanes, and prostaglandins, constitute these bioactive signals and are crucial for synaptic differentiation and plasticity [40]. ...
Our knowledge about the consumption of cannabinoids during pregnancy lacks consistent evidence to determine whether it compromises neurodevelopment. Addressing this task is challenging and complex since pregnant women display multiple confounding factors that make it difficult to identify the real effect of cannabinoids’ consumption. Recent studies shed light on this issue by using pluripotent stem cells of human origin, which can recapitulate human neurodevelopment. These revolutionary platforms allow studying how exogenous cannabinoids could alter human neurodevelopment without ethical concerns and confounding factors. Here, we review the information to date on the clinical studies about the impact of exogenous cannabinoid consumption on human brain development and how exogenous cannabinoids alter nervous system development in humans using cultured pluripotent stem cells as 2D and 3D platforms to recapitulate brain development.
... The different IN types migrate into the cortex via two main migratory routes: the intermediate zone (IZ) route is located above the germinal layers (ventricular and sub-ventricular zones) while the MZ route is close to the cortical surface (Lavdas et al., 1999;Nadarajah and Parnavelas, 2002). The choice of the migratory stream seems to depend on embryonic origins and cell identities (Kanatani et al., 2008;Antypa et al., 2011). For example, the MGE-derived interneurons PV and SST+ Martinotti cells reach the cortex via the MZ while non-Martinotti cells migrate via the IZ (Lim et al., 2018a). ...
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.
... In the cortex, the potent chemoattractive chemokine SDF1 (C-X-C motif chemokine 12 or Cxcl12) and its receptors Cxcr4 and Cxcr7 are necessary and sufficient to organize the cortical migratory streams (Tiveron et al., 2006;Li et al., 2008;López-Bendito et al., 2008;Sánchez-Alcañiz et al., 2011;Wang et al., 2011;Zarbalis et al., 2012). In contrast, transcriptomic analysis indicates that specification of interneuron diversity is established early during development and that interneurons in each stream display a specific genetic expression profile (Antypa et al., 2011;Mi et al., 2018). Interestingly, early specification seems to determine the choice of the migratory cortical route, indicating the presence of specific signals involved in sorting interneurons between the different migratory streams . ...
... For instance, a particular suptype of SST1 interneurons, the Martinotti cells, as well as the translaminar PV1 interneurons show a strong preference for migration through the MZ stream . In accordance with this model, several transcriptomic approaches have demonstrated that interneurons from different streams display different gene expression, including, interestingly, FLRT2 and FLRT3, which would allow these cells to sort out a specific migration route (Antypa et al., 2011;Lim et al., 2018). So far, however, evidence for specific mechanisms that could regulate the migration of interneurons through a particular stream is missing. ...
Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin+ interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through a repulsive mechanism. In support of such a conclusion, double knockouts deficient in the repulsive receptors for FLRTs, Unc5B and Unc5D, also display interneuron defects during development, similar to the FLRT2/FLRT3 mutants. Moreover, FLRT proteins are chemorepellent ligands for developing interneurons in vitro, an effect that is in part dependent on FLRT-Unc5 interaction. Together, we propose that FLRTs act through Unc5 receptors to control cortical interneuron distribution in a mechanism that involves cell repulsion.SIGNIFICANCE STATEMENT Disruption of inhibitory cortical circuits is responsible for some aspects of psychiatric disorders such as schizophrenia or autism. These defects include interneuron migration during development. A crucial step during this process is the formation of three transient migratory streams within the developing cortex that determine the timing of interneuron final positioning and the formation of functional cortical circuits in the adult. We report that FLRT proteins are required for the proper distribution of interneurons within the cortical migratory streams and for the final laminar allocation in the postnatal cortex. These results expand the multifunctional role of FLRTs during nervous system development in addition to the role of FLRTs in axon guidance and the migration of excitatory cortical neurons.
... DCX is a microtubule-associated protein necessary for correct tangential migration and laminar allocation in developing telecephalons in both mice and rats (Francis et al. 1999) Its coexpression with CB1 receptors indicates the possible role of CB1 receptors in neuronal migration (Saez et al. 2014). In the prelate/MZ, the superficial migrating zone of interneurons, CNR1 was shown to be strongly expressed on GAD-67 positive interneurons at E15.5 (Antypa et al. 2011). This observation further indicated that CB1 receptors are essential regulating factors in interneuron migration. ...
In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.
... Epha3 expression was increased in the mutant MGE at E15.5 (Figures 4A-A ), which explained why the LGE had very few MGE-derived cells, as enhanced Eph/ephrin signaling in the LGE VZ/SVZ increases the repulsive effect on migrating interneurons (Zimmer et al., 2008;Rudolph et al., 2010;Villar-Cerviño et al., 2015;Liu et al., 2018). Intracellular signaling molecule Ppp2r2c is mainly expressed in cortical interneurons in the MZ, whereas Rasgef1b is mainly expressed in cortical interneurons in the SVZ (Colasante et al., 2009;Antypa et al., 2011;Friocourt and Parnavelas, 2011). We found that the expression of Ppp2r2c in the cortical MZ was reduced, whereas the expression of Rasgef1b was greatly increased in the cortical SVZ of mutants compared with controls (Figures 4B-D ; Antypa et al., 2011). ...
... Intracellular signaling molecule Ppp2r2c is mainly expressed in cortical interneurons in the MZ, whereas Rasgef1b is mainly expressed in cortical interneurons in the SVZ (Colasante et al., 2009;Antypa et al., 2011;Friocourt and Parnavelas, 2011). We found that the expression of Ppp2r2c in the cortical MZ was reduced, whereas the expression of Rasgef1b was greatly increased in the cortical SVZ of mutants compared with controls (Figures 4B-D ; Antypa et al., 2011). Notably, these phenotypes were more prominent in Sp8/9 double mutants than in Sp9 single mutants (Figures 4A-D ), further suggesting that Sp8 supplements the role of Sp9 in regulating MGE-derived cortical interneuron migration. ...
... This finding explains why PV + cortical interneurons were severely reduced in the double mutant cortex compared with the single mutant cortex and indicate that Sp8 indeed has an important function in promoting MGE-derived cortical interneuron migration. The Ppp2r2c gene, encoding a subunit of protein phosphatase 2A, has a unique expression pattern in the embryonic mouse neocortex; interneurons in the cortical MZ express Ppp2r2c, but interneurons in the cortical SVZ do not (Colasante et al., 2009;Antypa et al., 2011;Friocourt and Parnavelas, 2011). Rasgef1b expression appeared to be limited to the cortical SVZ interneuron stream (Colasante et al., 2009;Antypa et al., 2011;Friocourt and Parnavelas, 2011). ...
Cortical interneurons are derived from the subpallium and reach the developing cortex through long tangential migration. Mature cortical interneurons are characterized by remarkable morphological, molecular, and functional diversity. The calcium-binding protein parvalbumin (PV) and neuropeptide somatostatin (SST) identify most medial ganglionic eminence (MGE)-derived cortical interneurons. Previously, we demonstrated that Sp9 plays a curial transcriptional role in regulating MGE-derived cortical interneuron development. Here, we show that SP8 protein is weekly expressed in the MGE mantle zone of wild type mice but upregulated in Sp9 null mutants. PV+ cortical interneurons were severely lost in Sp8/Sp9 double conditional knockouts due to defects in tangential migration compared with Sp9 single mutants, suggesting that Sp8/9 coordinately regulate PV+ cortical interneuron development. We provide evidence that Sp8/Sp9 activity is required for normal MGE-derived cortical interneuron migration, at least in part, through regulating the expression of EphA3, Ppp2r2c, and Rasgef1b.
... Chlorpyrifos was found to alter the proliferation, differentiation, and histone modifications of human neuroprogenitor cells in vitro [78]. In the mouse hippocampus, most of the CB1-expressing neurons are cholecystokininexpressing interneurons (CCK-INTs) [79,80]. Exposure to chlorpyrifos evoked a robust upregulation of cholecystokinin in PC12 cells in vitro [81]. ...
... To identify genes involved in migratory stream specification, we previously compared the gene expression profiles of cells in the pre-plate (PPL) zone with those of cells migrating through the IZ during early corticogenesis (E13.5). Our analysis identified several cadherin family members that showed differential expression, including Cdh8, which was present only in the IZ at this stage (Antypa et al. 2011), a finding recently supported by another study (Pensold and Zimmer 2018). ...
... We previously carried out a microarray analysis to identify genes that showed differential expression between the early tangential migratory streams, which may underlie the choice of pathway for migrating cortical interneurons (Antypa et al. 2011). This analysis identified several differentially expressed cadherin molecules, including Cdh8, which appeared to be expressed specifically in the IZ during early corticogenesis (E13.5). ...
Cortical interneurons are born in the ventral forebrain and migrate tangentially in two streams at the levels of the intermediate zone (IZ) and the pre-plate/marginal zone to the developing cortex where they switch to radial migration before settling in their final positions in the cortical plate. In a previous attempt to identify the molecules that regulate stream specification, we performed transcriptomic analysis of GFP-labelled interneurons taken from the two migratory streams during corticogenesis. A number of cadherins were found to be expressed differentially, with Cadherin-8 (Cdh8) selectively present in the IZ stream. We verified this expression pattern at the mRNA and protein levels on tissue sections and found approximately half of the interneurons of the IZ expressed Cdh8. Furthermore, this cadherin was also detected in the germinal zones of the subpallium, suggesting that it might be involved not only in the migration of interneurons but also in their generation. Quantitative analysis of cortical interneurons in animals lacking the cadherin at E18.5 revealed a significant increase in their numbers. Subsequent functional in vitro experiments showed that blocking Cdh8 function led to increased cell proliferation, with the opposite results observed with over-expression, supporting its role in interneuron generation.
... Il apparaît en effet que les interneurones ne se distribuent pas aléatoirement dans les différents flux, mais montrent à l'inverse des préférences pour l'un ou l'autre. Une étude d'Antypa et al. montre des profils d'expression génique différents pour les interneurones migrant dans la ZM ou la ZSV, et en particulier pour des récepteurs de molécules de guidage (Antypa et al., 2011). Par ailleurs, une étude a montré que des interneurones où l'interaction du récepteur aux intégrines α3 avec Nétrine 1 est inhibée (par invalidation de ces deux facteurs) ne parviennent plus à migrer dans la ZM, mais semblent migrer parfaitement dans la ZSV (Stanco et al., 2009). ...
Dans le cerveau en développement, les interneurones corticaux effectuent une longue migration avant de se positionner dans le cortex et s’intégrer dans les réseaux corticaux dont ils régulent l’activité. Différents facteurs chimiques ont été impliqués dans le guidage de ces cellules, mais l’influence des propriétés physiques de l’environnement dans lequel ils naviguent reste peu connue. Il a été montré que les indices topographiques peuvent guider le mouvement de nombreux types cellulaires, un processus appelé guidage par contact. Mes travaux de thèse ont ainsi cherché à tester et comprendre l’influence de la topographie de l’environnement sur la migration des interneurones corticaux. En utilisant un système expérimental de substrats microstructurés, nous avons mis en évidence pour la première fois l’existence du guidage par contact pour ces cellules. En testant deux types de micro-plots, nous avons établi qu’un changement de forme des structures influence de manière importante l’orientation, la morphologie, l’organisation du cytosquelette et le comportement dynamique des cellules. En particulier, les interneurones en migration entre des plots carrés adoptent majoritairement une morphologie allongée et peu branchée, associée à un mouvement lent et dirigé. A l’inverse, des cellules entre des plots ronds sont plus courtes et montrent un branchement important associé à un mouvement dynamique mais aléatoire. Plus généralement, nous montrons in vitro que la topographie génère des contraintes spatiales globales qui promeuvent la mise en place de différents états cellulaires morphologiques et dynamiques, soulignant ainsi la potentielle importance de ce type d’indices in vivo.
... Upon Lhx1 deletion, we found reduced numbers of POA-deriving cells in the upper parts of the developing cortex while an augmented proportion of cells migrated deeply. Several studies suggested changes in expression profiles of cortical interneurons when entering the cortex to maintain responsiveness to the different environmental cues in the cortical compartment (Nguyen et al. 2001;Ferguson et al. 2005;Crandall et al. 2007;Stanco et al. 2009;Antypa et al. 2011). Despite the restricted Lhx1 mRNA expression to early post-mitotic POA cells, Lhx1 deficiency affected the migration pattern in the cortex. ...
The delicate balance of excitation and inhibition is crucial for proper function of the cerebral cortex, relying on the accurate
number and subtype composition of inhibitory gamma-aminobutyric (GABA)-expressing interneurons. Various intrinsic and
extrinsic factors precisely orchestrate their multifaceted development including the long-range migration from the basal
telencephalon to cortical targets as well as interneuron survival throughout the developmental period. Particularly
expressed guidance receptors were described to channel the migration of cortical interneurons deriving from the medial
ganglionic eminence (MGE) and the preoptic area (POA) along distinct routes. Hence, unveiling the regulatory genetic
networks controlling subtype-specific gene expression profiles is key to understand interneuron-specific developmental
programs and to reveal causes for associated disorders. In contrast to MGE-derived interneurons, little is known about the
transcriptional networks in interneurons born in the POA. Here, we provide first evidence for the LIM-homeobox
transcription factor LHX1 as a crucial key player in the post-mitotic development of POA-derived cortical interneurons. By
transcriptional regulation of related genes, LHX1 modulates their survival as well as the subtype-specific expression of
guidance receptors of the Eph/ephrin family, thereby affecting directional migration and layer distribution in the adult
cortex.
... In order to identify the genes involved in migratory stream specification, we compared the gene expression profiles of cells in the preplate layer (PPL) with those of cells migrating through the intermediate zone (IZ) during early corticogenesis. Our analysis identified several cadherin family members that showed differential expression, including Cdh13 (also known as T-cadherin) which was present only in the PPL (Antypa et al. 2011). ...
... At E13.5, Cdh13 mRNA expression shows a gradient within the PPL being highest at the level of the corticostriatal junction and lowest in the hippocampus ; this is in agreement with our previous microarray study (Antypa et al. 2011). In the basal telencephalon, Cdh13 mRNA is expressed weakly in the preoptic area (POA). ...
... Our analysis showed that Cdh13 is not present in interneurons during the early phase (E13.5) of corticogenesis. This finding is in disagreement with our previous microarray study where we showed expression of Cdh13 in the PPL (Antypa et al. 2011). However, interneurons were not purified from the isolated PPL in this study, so it is possible that other cells or blood vessels, which appear to express Cdh13, could have been isolated together with interneurons, thus contaminating the sample. ...
Cortical interneurons are generated in the ganglionic eminences and migrate through the ventral and dorsal telencephalon before finding their final positions within the cortical plate. During early stages of migration, these cells are present in two well-defined streams within the developing cortex. In an attempt to identify candidate genes which may play a role in interneuron stream specification, we previously carried out a microarray analysis which identified a number of cadherin receptors that were differentially expressed in these streams, including Cadherin-13 (Cdh13). Expression analysis confirmed Cdh13 to be present in the preplate layer at E13.5 and, later in development, in some cortical interneurons and pyramidal cells. Analysis of Cdh13 knockout mice at E18.5, but not at E15.5, showed a reduction in the number of interneurons and late born pyramidal neurons and a concomitant increase in apoptotic cells in the cortex. These observations were confirmed in dissociated cell cultures using overexpression and short interfering RNAs (siRNAs) constructs and dominant negative inhibitory proteins. Our findings identified a novel protective role for Cdh13 in cortical neuron development.
