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Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue themigration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans. [ABSTRACT FROM AUTHOR]

Communication between the nervous and immune system is crucial for development, homeostasis and response to injury. Before the onset of neurogenesis, microglia populate the central nervous system, serving as resident immune cells over the course of life. Here, we describe new roles of an uncharacterized transcript upregulated by neurogenic progenitors during mouse corticogenesis: 4931414P19Rik (hereafter named P19). Overexpression of P19 cell-extrinsically inhibited neuronal migration and acted as chemoattractant of microglial cells. Interestingly, effects on neuronal migration were found to result directly from P19 secretion by neural progenitors triggering microglia accumulation within the P19 targeted area. Our findings highlight the crucial role of microglia during brain development and identify P19 as a previously unreported player in the neuro-immune crosstalk. [ABSTRACT FROM AUTHOR]

In the developing hindbrain, facial branchiomotor (FBM) neurons migrate caudally from rhombomere 4 (r4) to r6 to establish the circuit that drives jaw movements. Although the mechanisms regulating initiation of FBM neuron migration are well defined, those regulating directionality are not. In mutants lacking the Wnt/planar cell polarity (PCP) component Celsr1, many FBM neurons inappropriately migrate rostrally into r3. We hypothesized that Celsr1 normally blocks inappropriate rostral migration of FBM neurons by suppressing chemoattraction towards Wnt5a in r3 and successfully tested this model. First, FBM neurons in Celsr1; Wnt5a double mutant embryos never migrated rostrally, indicating that inappropriate rostral migration in Celsr1 mutants results from Wnt5a-mediated chemoattraction, which is suppressed in wild-type embryos. Second, FBM neurons migrated rostrally toward Wnt5a-coated beads placed in r3 of wild-type hindbrain explants, suggesting that excess Wnt5a chemoattractant can overcome endogenous Celsr1-mediated suppression. Third, rostral migration of FBM neurons was greatly enhanced in Celsr1 mutants overexpressing Wnt5a in r3. These results reveal a novel role for a Wnt/PCP component in regulating neuronal migration through suppression of chemoattraction. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO), the hypoxia-inducible hematopoietic hormone, has well-established neuroprotective/neurotrophic roles in the developing central nervous system and the therapeutic potential of EPO has been widely explored in clinical studies for the treatment of perinatal hypoxic brain lesion, as well as prematurity. Here, we reveal that both EPO and Epo receptor (EPOR) are expressed in the developing rat somatosensory cortex during radial migration and laminar positioning of granular and supragranular neurons. Experimental deregulation of EPO signaling using genetic approaches results in aberrant migration, as well as permanent neuronal misplacement leading to abnormal network activity and protracted sensory behavioral deficits. We identify ERK as the downstream effector of the EPO signaling pathway for neuronal migration. These findings reveal a crucial role for endogenous EPO signaling in neuronal migration, and offer important insights for understanding how the temporary deregulation of EPO could result in migration defects that lead to abnormal behavior in the adult. [ABSTRACT FROM AUTHOR]

The microtubule motor cytoplasmic dynein contributes to radial migration of newborn pyramidal neurons in the developing neocortex. Here, we show that AMP-activated protein kinase (AMPK) mediates the nucleus-centrosome coupling, a key process for radial neuronal migration that relies on dynein. Depletion of the catalytic subunit of AMPK in migrating neurons impairs this coupling as well as neuronal migration. AMPK shows overlapping subcellular distribution with cytoplasmic dynein and the two proteins interact with each other. Pharmacological inhibition or activation of AMPK modifies the phosphorylation states of dynein intermediate chain (DIC) and dynein functions. Furthermore, AMPK phosphorylates DIC at Ser81. Expression of a phospho-resistant mutant of DIC retards neuronal migration in a similar way to AMPK depletion. Conversely, expression of the phospho-mimetic mutant of DIC alleviates impaired neuronal migration caused by AMPK depletion. Thus, AMPK-regulated dynein function via Ser81 DIC phosphorylation is crucial for radial neuronal migration. [ABSTRACT FROM AUTHOR]

Neocortex development during embryonic stages requires the precise control of mRNA metabolism. Human antigen R (HuR) is a well-studied mRNA-binding protein that regulates mRNA metabolism, and it is highly expressed in the neocortex during developmental stages. Deletion of HuR does not impair neural progenitor cell proliferation or differentiation, but it disturbs the laminar structure of the neocortex. We report that HuR is expressed in postmitotic projection neurons during mouse brain development. Specifically, depletion of HuR in these neurons led to a mislocalization of CDP+ neurons in deeper layers of the cortex. Time-lapse microscopy showed that HuR was required for the promotion of cell motility in migrating neurons. PCR array identified profilin 1 (Pfn1) mRNA as a major binding partner of HuR in neurons. HuR positively mediated the stability of Pfn1 mRNA and influenced actin polymerization. Overexpression of Pfn1 successfully rescued the migration defects of HuR-deleted neurons. Our data reveal a post-transcriptional mechanism that maintains actin dynamics during neuronal migration. [ABSTRACT FROM AUTHOR]

The precise migration of cortical interneurons is essential for the formation and function of cortical circuits, and disruptions to this key developmental process are implicated in the etiology of complex neurodevelopmental disorders, including schizophrenia, autism and epilepsy.We have recently identified the Jun N-terminal kinase (JNK) pathway as an important mediator of cortical interneuron migration in mice, regulating the proper timing of interneuron arrival into the cortical rudiment. In the current study, we demonstrate a vital role for JNK signaling at later stages of corticogenesis, when interneurons transition from tangential to radial modes of migration. Pharmacological inhibition of JNK signaling in ex vivo slice cultures caused cortical interneurons to rapidly depart frommigratory streams and prematurely enter the cortical plate. Similarly, genetic loss of JNK function led to precocious stream departure ex vivo, and stream disruption, morphological changes and abnormal allocation of cortical interneurons in vivo. These data suggest that JNK signaling facilitates the tangential migration and laminar deposition of cortical interneurons, and further implicates the JNK pathway as an important regulator of cortical development. [ABSTRACT FROM AUTHOR]

The polarity and organization of radial glial cells (RGCs), which serve as both stem cells and scaffolds for neuronal migration, are crucial for cortical development. However, the cytoskeletal mechanisms that drive radial glial outgrowth and maintain RGC polarity remain poorly understood. Here, we show that the Arp2/3 complex -- the unique actin nucleator that produces branched actin networks -- plays essential roles in RGC polarity and morphogenesis. Disruption of the Arp2/3 complex in murine RGCs retards process outgrowth toward the basal surface and impairs apical polarity and adherens junctions. Whereas the former is correlated with an abnormal actin-based leading edge, the latter is consistent with blockage in membrane trafficking. These defects result in altered cell fate, disrupted cortical lamination and abnormal angiogenesis. In addition, we present evidence that the Arp2/3 complex is a cell-autonomous regulator of neuronal migration. Our data suggest that Arp2/3-mediated actin assembly might be particularly important for neuronal cell motility in a soft or poorly adhesive matrix environment. [ABSTRACT FROM AUTHOR]

In reeler mutant mice, which are deficient in reelin (Reln), the lamination of the cerebral cortex is disrupted. Reelin signaling induces phosphorylation of LIM kinase 1, which phosphorylates the actin-depolymerizing protein cofilin in migrating neurons. Conditional cofilin mutants show neuronal migration defects. Thus, both reelin and cofilin are indispensable during cortical development. To analyze the effects of cofilin phosphorylation on neuronal migration we used in utero electroporation to transfect E14.5 wild-type cortical neurons with pCAG-EGFP plasmids encoding either a nonphosphorylatable form of cofilin 1 (cofilinS3A), a pseudophosphorylated form (cofilinS3E) or wild-type cofilin 1 (cofilinWT). Wild-type controls and reeler neurons were transfected with pCAG-EGFP. Real-time microscopy and histological analyses revealed that overexpression of cofilinWT and both phosphomutants induced migration defects and morphological abnormalities of cortical neurons. Of note, reeler neurons and cofilinS3A-and cofilinS3E-transfected neurons showed aberrant backward migration towards the ventricular zone. Overexpression of cofilinS3E, the pseudophosphorylated form, partially rescued the migration defect of reeler neurons, as did overexpression of Limk1. Collectively, the results indicate that reelin and cofilin cooperate in controlling cytoskeletal dynamics during neuronal migration. [ABSTRACT FROM AUTHOR]

The mature vertebrate retina is a highly ordered neuronal network of cell bodies and synaptic neuropils arranged in distinct layers. Little, however, is known about the emergence of this spatial arrangement. Here, we investigate how the three main types of retinal inhibitory neuron (RIN) - horizontal cells (HCs), inner nuclear layer amacrine cells (iACs) and displaced amacrine cells (dACs) - reach their specific laminar positions during development. Using in vivo time-lapse imaging of zebrafish retinas, we show that RINs undergo distinct phases of migration. The first phase, common to all RINs, is bipolar migration directed towards the apicobasal centre of the retina. All RINs then transition to a less directionally persistent multipolar phase of migration. Finally, HCs, iACs and dACs each undergo cell type-specific migration. In contrast to current hypotheses, we find that most dACs send processes into the forming inner plexiform layer (IPL) before migrating through it and inverting their polarity. By imaging and quantifying the dynamics of HCs, iACs and dACs from birth to final position, this study thus provides evidence for distinct and new migration patterns during retinal lamination and insights into the initiation of IPL formation. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH) neurons are born in the nasal placode and migrate along olfactory and vomeronasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated by Slit2 and Robo3, members of the axon guidance Slit ligand and Robo receptor families. Mice lacking Slit2 or Robo3 have a reduced number of GnRH neurons in the forebrain, but a normal complement of their supporting axons, pointing to a direct role for these molecules in GnRH neuron migration. [ABSTRACT FROM AUTHOR]

Neuronal migration, a key event during brain development, remains largely unexplored in the mesencephalon, where dopaminergic (DA) and GABA neurons constitute two major neuronal populations. Here we study the migrational trajectories of DA and GABA neurons and show that they occupy ventral mesencephalic territory in a temporally and spatially specific manner. Our results from the Pitx3-deficient aphakia mouse suggest that pre-existing DA neurons modulate GABA neuronal migration to their final destination, providing novel insights and fresh perspectives concerning neuronal migration and connectivity in the mesencephalon in normal as well as diseased brains. [ABSTRACT FROM AUTHOR]

The cerebral neocortex is segregated into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection (pyramidal) neurons and inhibitory interneurons. Development of the neocortex requires the orchestrated execution of a series of crucial processes, including the migration of young neurons into appropriate positions within the nascent neocortex, and the acquisition of layer-specific neuronal identities and axonal projections. Here, we discuss emerging evidence supporting the notion that the migration and final laminar positioning of cortical neurons are also co-regulated by cell type- and layerspecific transcription factors that play concomitant roles in determining the molecular identity and axonal connectivity of these neurons. These transcriptional programs thus provide direct links between the mechanisms controlling the laminar position and identity of cortical neurons. [ABSTRACT FROM AUTHOR]

During corticogenesis, the regulation of neuronal migration is crucial for the functional organization of the neocortex. Glutamatergic neurons are major excitatory components of the mammalian neocortex. In order to elucidate the specific molecular mechanisms underlying their development, we used single-cell microarray analysis to screen for mouse genes that are highly expressed in developing glutamatergic neurons. We identified dpy-19-like 1 (Dpy19l1), a homolog of C. elegans dpy-19, which encodes a putative multi-transmembrane protein shown to regulate directed migration of Q neuroblasts in C. elegans. At embryonic stages Dpy19l1 is highly expressed in glutamatergic neurons in the mouse cerebral cortex, whereas in the subpallium, where GABAergic neurons are generated, expression was below detectable levels. Downregulation of Dpy19l1 mediated by shRNA resulted in defective radial migration of glutamatergic neurons in vivo, which was restored by the expression of shRNAinsensitive Dpy19l1. Many Dpy19l1-knockdown cells were aberrantly arrested in the intermediate zone and the deep layer and, additionally, some extended single long processes towards the pial surface. Furthermore, we observed defective radial migration of bipolar cells in Dpy19l1-knockdown brains. Despite these migration defects, these cells correctly expressed Cux1, which is a marker for upper layer neurons, suggesting that Dpy19l1 knockdown results in migration defects but does not affect cell type specification. These results indicate that Dpy19l1 is required for the proper radial migration of glutamatergic neurons, and suggest an evolutionarily conserved role for the Dpy19 family in neuronal migration. [ABSTRACT FROM AUTHOR]

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ)-olfactory bulb pathway. The molecular regulation of this neurogenic circuit is poorly understood. Because the components for retinoid signaling are present in this pathway, we examined the influence of retinoic acid (RA) on postnatal SVZ-olfactory bulb neurogenesis. Using both SVZ neurosphere stem cell and parasagittal brain slice cultures derived from postnatal mouse, we found that RA exposure increased neurogenesis by enhancing the proliferation and neuronal differentiation of forebrain SVZ neuroblasts. The RA precursor retinol had a similar effect, which was reversed by treating cultures with the RA synthesis inhibitor disulfiram. Electroporation of dominant-negative retinoid receptors into the SVZ of slice cultures also blocked neuroblast migration to the olfactory bulb and altered the morphology of the progenitors. Moreover, the administration of disulfiram to neonatal mice decreased in vivo cell proliferation in the striatal SVZ. These results indicate that RA is a potent mitogen for SVZ neuroblasts and is required for their migration to the olfactory bulb. The regulation of multiple steps in the SVZ-olfactory bulb neurogenic pathway by RA suggests that manipulation of retinoid signaling is a potential therapeutic strategy to augment neurogenesis after brain injury. [ABSTRACT FROM AUTHOR]

In the developing vertebrate hindbrain, the characteristic trajectory of the facial (nVII) motor nerve is generated by caudal migration of the nVII motor neurons. The nVII motor neurons originate in rhombomere (r) 4, and migrate caudally into r6 to form the facial motor nucleus. In this study, using a transgenic zebrafish line that expresses green fluorescent protein (GFP) in the cranial motor neurons, we isolated two novel mutants, designated landlocked (llk) and off-road (ord), which both show highly specific defects in the caudal migration of the nVII motor neurons. We show that the landlocked locus contains the gene scribble1 (scrb1), and that its zygotic expression is required for migration of the nVII motor neurons mainly in a non cell-autonomous manner. Taking advantage of the viability of the llk mutant embryos, we found that maternal expression of scrb1 is required for convergent extension (CE) movements during gastrulation. Furthermore, we show a genetic interaction between scrb1 and trilobite(tri)/strabismus(stbm) in CE. The dual roles of the scrb1 gene in both neuronal migration and CE provide a novel insight into the underlying mechanisms of cell movement in vertebrate development. [ABSTRACT FROM AUTHOR]

The cytoarchitecture of the hindbrain results from precise and co-ordinated sequences of neuronal migrations. Here, we show that reelin, an extracellular matrix protein involved in neuronal migration during CNS development, is necessary for an early, specific step in the migration of several hindbrain nuclei. We identified two cell populations not previously known to be affected in reeler mutants that show a common migratory defect: the olivocochlear efferent neurons and the facial visceral motor nucleus. In control embryos, these cells migrate first toward a lateral position within the neural tube, and then parallel to the glial cell processes, to a ventral position where they settle close to the pial surface. In reeler mutants, the first migration is not affected, but the neurons are unable to reach the pial surface and remain in an ectopic position. Indeed, this is the first evidence that the migration of specific hindbrain nuclei can be divided into two parts: a reelin-independent and a reelin-dependent migration. We also show that reelin is expressed at high levels at the final destination of the migratory process, while the reelin intracellular effector Dab1 was expressed by cell groups that included the two populations affected. Mice mutant at the Dab1 locus, called scrambler, exhibit the same phenotype, a failure of final migration. However, examination of mice lacking both reelin receptors, ApoER2 and VLDLR, did not reveal the same phenotype, suggesting involvement of an additional reelin-binding receptor. In the hindbrain, reelin signaling might alter the adhesive properties of efferent neurons and their ability to respond to directional cues, as has been suggested for the migration of olfactory bulb precursors. [ABSTRACT FROM AUTHOR]

Reelin is required for the proper positioning of neurons in the cerebral cortex. In the reeler mutant lacking reelin, the granule cells of the dentate gyrus fail to form a regular, densely packed cell layer. Recent evidence suggests that this defect is due to the malformation of radial glial processes required for granule cell migration. Here, we show that recombinant reelin in the medium significantly increases the length of GFAP-positive radial glial fibers in slice cultures of reeler hippocampus, but does not rescue either radial glial fiber orientation or granule cell lamination. However, rescue of radial glial fiber orientation and granule cell lamination was achieved when reelin was present in the normotopic position provided by wild-type co-culture, an effect that is blocked by the CR-50 antibody against reelin. These results indicate a dual function of reelin in the dentate gyms, as a differentiation factor for radial glial cells and as a positional cue for radial fiber orientation and granule cell migration. [ABSTRACT FROM AUTHOR]

Morphogenesis of the central nervous system relies in large part upon the correct migration of neuronal cells from birthplace to final position. Two general modes of migration govern CNS morphogenesis: radial, which is mostly glia-guided and topologically relatively simple; and tangential, which often involves complex movement of neurons in more than one direction. We describe the consequences of loss of function of presenilin 1 on these fundamental processes. Previous studies of the central nervous system in presenilin 1 homozygote mutant embryos identified a premature neuronal differentiation that is transient and localized, with cortical dysplasia at later stages. We document widespread effects on CNS morphogenesis that appear strongly linked to defective neuronal migration. Loss of presenilin 1 function perturbs both radial and tangential migration in cerebral cortex, and several tangential migratory pathways in the brainstem. The inability of cells to execute their migratory trajectories affects cortical lamination, formation of the facial branchiomotor nucleus, the spread of cerebellar granule cell precursors to form the external granule layer and development of the pontine nuclei. Finally, overall morphogenesis of the mid-hindbrain region is abnormal, resulting in incomplete midline fusion of the cerebellum and overgrowth of the caudal midbrain. These observations indicate that in the absence of presenilin 1 function, the ability of a cell to move can be severely impaired regardless of its mode of migration, and, at a grosser level, brain morphogenesis is perturbed. Our results demonstrate that presenilin 1 plays a much more important role in brain development than has been assumed, consistent with a pleiotropic involvement of this molecule in cellular signaling. [ABSTRACT FROM AUTHOR]

As many studies have focused on the mechanisms of motoneuron specification, little is known about the factors that control the subsequent development of postmitotic motoneurons. Previously, we showed that the transcription factor Nkx6.1 is required for the early specification of somatic motoneuron progenitors in the spinal cord. Our present analysis of hindbrain motoneuron development in Nkx6.1-deficient mouse embryos reveals that the early specification of branchio-motoneurons is independent of Nkx6.1 function, but that it is required for their subsequent development. In Nkx6.1 mutant mice, we observed defects in the migration, as well as in the axon projections of branchio-motoneurons. A detailed analysis of the migratory defect in facial branchio-motoneurons reveals ectopic expression of the cell surface receptors Ret and Unc5h3 in premigratory neurons, but no changes in the rhombomeric environment. Taken together, our findings demonstrate a requirement for Nkx6.1 in the development of postmitotic motoneurons, and suggest a cell-autonomous function in the control of branchio-motoneuron migration. [ABSTRACT FROM AUTHOR]

Neuronal migration is crucial for the construction of neuronal architecture such as layers and nuclei. Most inhibitory interneurons in the neocortex derive from the basal forebrain and migrate tangentially; however, little is known about the mode of migration of these neurons in the cortex. We used glutamate decarboxylase (Gad)67-green fluorescent protein (GFP) knock-in embryonic mice with expression of GFP in gamma-aminobutyric acid (GABA)-ergic neurons and performed time-lapse analysis. In coronal slices, many GFP-positive neurons in the lower intermediate zone (IZ) and subventricular zone (SVZ) showed robust tangential migration from lateral to medial cortex, while others showed radial and non-radial migration mostly towards the pial surface. In flat-mount preparations, GFP-positive neurons of the marginal zone (MZ) showed multidirectional tangential migration. Some of these neurons descended toward the cortical plate (CP). Intracortical migration of these neurons was largely unaffected by a treatment that cleaves glycosylphosphatidylinositol (GPI) anchors. These findings suggest that tangential migration of cortical interneurons from lateral to medial cortex predominantly occurs in the IZ/SVZ and raise the possibility that a part of the pial surface-directed neurons in the IZ/SVZ reach the MZ, whereby they spread into the whole area of the cortex. At least a part of these neurons may descend toward the CP. Our results also suggest that intracortical migration of GABAergic neurons occurs independent of GPI-anchored proteins. [ABSTRACT FROM AUTHOR]

Hox genes are instrumental in assigning segmental identity in the developing hindbrain. Auto-, cross- and pararegulatory interactions help establish and maintain their expression. To understand to what extent such regulatory interactions shape neuronal patterning in the hindbrain, we analysed neurogenesis, neuronal differentiation and motoneuron migration in Hoxa1, Hoxb1 and Hoxb2 mutant mice. This comparison revealed that neurogenesis and differentiation of specific neuronal subpopulations in r4 was impaired in a similar fashion in all three mutants, but with different degrees of severity. In the Hoxb1 mutants, neurons derived from the presumptive r4 territory were respecified towards an r2-like identity. Motoneurons derived from that territory resembled trigeminal motoneurons in both their migration patterns and the expression of molecular markers. Both migrating motoneurons and the resident territory underwent changes consistent with a switch from an r4 to r2 identity. Abnormally migrating motoneurons initially formed ectopic nuclei that were subsequently cleared. Their survival could be prolonged through the introduction of a block in the apoptotic pathway. The Hoxa1 mutant phenotype is consistent with a partial misspecification of the presumptive r4 territory that results from partial Hoxb1 activation. The Hoxb2 mutant phenotype is a hypomorph of the Hoxb1 mutant phenotype, consistent with the overlapping roles of these genes in facial motoneuron specification. Therefore, we have delineated the functional requirements in hindbrain neuronal patterning that follow the establishment of the genetic regulatory hierarchy between Hoxa1, Hoxb1 and Hoxb2. [ABSTRACT FROM AUTHOR]

The facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration. [ABSTRACT FROM AUTHOR]

The Drosophila optic lobe comprises a wide variety of neurons, which form laminar neuropiles with columnar units and topographic projections from the retina. The Drosophila optic lobe shares many structural characteristics with mammalian visual systems. However, little is known about the developmental mechanisms that produce neuronal diversity and organize the circuits in the primary region of the optic lobe, the medulla. Here, we describe the key features of the developing medulla and report novel phenomena that could accelerate our understanding of the Drosophila visual system. The identities of medulla neurons are pre-determined in the larval medulla primordium, which is subdivided into concentric zones characterized by the expression of four transcription factors: Drifter, Runt, Homothorax and Brain-specific homeobox (Bsh). The expression pattern of these factors correlates with the order of neuron production. Once the concentric zones are specified, the distribution of medulla neurons changes rapidly. Each type of medulla neuron exhibits an extensive but defined pattern of migration during pupal development. The results of clonal analysis suggest homothorax is required to specify the neuronal type by regulating various targets including Bsh and cell-adhesion molecules such as N-cadherin, while drifter regulates a subset of morphological features of Drifter-positive neurons. Thus, genes that show the concentric zones may form a genetic hierarchy to establish neuronal circuits in the medulla. [ABSTRACT FROM AUTHOR]

Numerous motile cell functions depend on signaling from the cytoskeleton to the nucleus. Myocardin-related transcription factors (MRTFs) translocate to the nucleus in response to actin polymerization and cooperate with serum response factor (Srf) to regulate the expression of genes encoding actin and other components of the cytoskeleton. Here, we show that MRTF-A (Mkl1) and MRTF-B (Mkl2) redundantly control neuronal migration and neurite outgrowth during mouse brain development. Conditional deletion of the genes encoding these Srf coactivators disrupts the formation of multiple brain structures, reflecting a failure in neuronal actin polymerization and cytoskeletal assembly. These abnormalities were accompanied by dysregulation of the actin-severing protein gelsolin and Pctaire1 (Cdk16) kinase, which cooperates with Cdk5 to initiate a kinase cascade that governs cytoskeletal rearrangements essential for neuron migration and neurite outgrowth. Thus, the MRTF/Srf partnership interlinks two key signaling pathways that control actin treadmilling and neuronal maturation, thereby fulfilling a regulatory loop that couples cytoskeletal dynamics to nuclear gene transcription during brain development. [ABSTRACT FROM AUTHOR]

The Polycomb repression complex 2 (PRC2) methylates histone H3 lysine 27 at target genes to modify gene expression, and this mark is recognized by PRC1, which ubiquitylates histone H2A. In Caenorhabditis elegans, a complex of the MES-2, MES-3 and MES-6 proteins is functionally analogous to the PRC2 complex, but the functional analog of PRC1, and indeed whether C. elegans has such a complex, has been unclear. We describe here that MIG-32 and SPAT-3A are functional analogs of PRC1 in C. elegans, where they are required for neuronal migrations and during vulval development. mig-32 and spat-3 mutants are defective in H2A ubiquitylation, and have nervous system defects that partially overlap with those of mes mutants. However, unlike the mes mutants, mig-32 and spat-3 mutants are fertile, suggesting that PRC1 function is not absolutely required in the germline for essential functions of PRC2. [ABSTRACT FROM AUTHOR]

Current models of chemotaxis during neuronal migration and axon guidance propose that directional sensing relies on growth cone dynamics. According to this view, migrating neurons and growing axons are guided to their correct targets by steering the growth cone in response to attractive and repulsive cues. Here, we have performed a detailed analysis of the dynamic behavior of individual neurons migrating tangentially in telencephalic slices using high-resolution time-lapse videomicroscopy. We found that cortical interneurons consistently display branched leading processes as part of their migratory cycle, a feature that seems to be common to many other populations of GABAergic neurons in the brain and spinal cord. Analysis of the migratory behavior of individual cells suggests that interneurons respond to chemoattractant signals by generating new leading process branches that are better aligned with the source of the gradient, and not by reorienting previously existing branches. Moreover, experimental evidence revealed that guidance cues influence the angle at which new branches emerge. This model is further supported by pharmacological experiments in which inhibition of branching blocked chemotaxis, suggesting that this process is an essential component of the mechanism controlling directional guidance. These results reveal a novel guidance mechanism during neuronal migration that might be extensively used in brain development. [ABSTRACT FROM AUTHOR]

An abstract of the article "Temporal regulation of ephrin/Eph signalling is required for the spatial pattering of the mammalian striatum," by Lara Passante, Nicolas Gaspard, Mélanie Degraeve, Jonas Frisén, Klas Kullander, Viviane De Maertelaer and Pirre Vanderhaegen.

Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration. [ABSTRACT FROM AUTHOR]

Reelin, its lipoprotein receptors [very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (ApoER2; also known as Lrp8)], and the cytoplasmic adaptor protein disabled 1 (Dab1) are important for the correct formation of layers in the cerebral cortex. Reeler mice lacking the reelin protein show altered radial neuronal migration resulting in an inversion of cortical layers. ApoER2 Vldlr double-knockout mutants and Dab1 mutants show a reeler-like phenotype, whereas milder phenotypes are found if only one of the two lipoprotein receptors for reelin is absent. However, the precise role of the individual reelin receptors in neuronal migration remained unclear. In the study reported here, we performed fate mapping of newly generated cortical neurons in single and double receptor mutants using bromodeoxyuridine-labeling and layer-specific markers. We present evidence for divergent roles of the two reelin receptors Vldlr and ApoER2, with Vldlr mediating a stop signal for migrating neurons and ApoER2 being essential for the migration of late generated neocortical neurons. [ABSTRACT FROM AUTHOR]

The mammalian cerebral cortex consists of six layers that are generated via coordinated neuronal migration during the embryonic period. Recent studies identified specific phases of radial migration of cortical neurons. After the final division, neurons transform from a multipolar to a bipolar shape within the subventricular zone-intermediate zone (SVZ-IZ) and then migrate along radial glial fibres. Mice lacking Cdk5 exhibit abnormal corticogenesis owing to neuronal migration defects. When we introduced GFP into migrating neurons at E14.5 by in utero electroporation, we observed migrating neurons in wild-type but not in Cdk5-/- embryos after 3-4 days. Introduction of the dominant-negative form of Cdk5 into the wild-type migrating neurons confirmed specific impairment of the multipolar-to-bipolar transition within the SVZ-IZ in a cell-autonomous manner. Cortex-specific Cdk5 conditional knockout mice showed inverted layering of the cerebral cortex and the layer V and callosal neurons, but not layer VI neurons, had severely impaired dendritic morphology. The amount of the dendritic protein Map2 was decreased in the cerebral cortex of Cdk5-deficient mice, and the axonal trajectory of cortical neurons within the cortex was also abnormal. These results indicate that Cdk5 is required for proper multipolar-to-bipolar transition, and a deficiency of Cdk5 results in abnormal morphology of pyramidal neurons. In addition, proper radial neuronal migration generates an inside-out pattern of cerebral cortex formation and normal axonal trajectories of cortical pyramidal neurons. [ABSTRACT FROM AUTHOR]

Early B-cell factor 2 (EBF2) is one of four mammalian members of an atypical helix-loop-helix transcription factor family (COE). COE proteins have been implicated in various aspects of nervous and immune system development. We and others have generated and described mice carrying a null mutation of Ebf2, a gene previously characterized in the context of Xenopus laevis primary neurogenesis and neuronal differentiation. In addition to deficits in neuroendocrine and olfactory development, and peripheral nerve maturation, Ebf2 null mice feature an ataxic gait and obvious motor deficits associated with clear-cut abnormalities of cerebellar development. The number of Purkinje cells (PCs) in the Ebf2 null is markedly decreased, resulting in a small cerebellum with notable foliation defects, particularly in the anterior vermis. We show that this stems from the defective migration of a molecularly defined PC subset that subsequently dies by apoptosis. Part of the striped cerebellar topography is disrupted due to cell death and, in addition, many of the surviving PCs, that would normally adopt a zebrin II-negative phenotype, transdifferentiate to Zebrin II-positive, an unprecedented finding suggesting that Ebf2 is required for the establishment of a proper cerebellar cortical map. [ABSTRACT FROM AUTHOR]

Most GABAergic interneurons originate from the basal forebrain and migrate tangentially into the cortex. The migratory pathways and mode of interneuron migration within the developing cerebral cortex, however, previously was largely unknown. Time-lapse imaging and in vivo labelling with glutamate decarboxylase (GAD)67-green fluorescence protein (GFP) knock-in embryonic mice with expression of GFP in gamma-aminobutyric acid (GABA)ergic neurons indicated that multidirectional tangential (MDT) migration of interneurons takes place in both the marginal zone (MZ) and the ventricular zone (VZ) of the cortex. Quantitative analysis of migrating interneurons showed that rostrocaudally migrating neurons outnumber those migrating mediolaterally in both of these zones. In vivo labelling with a lipophilic dye showed that the MDT migration in the MZ occurs throughout the cortex over distances of up to 3 mm during a period of a few days. These results indicate that MZ cortical interneurons undergo a second phase of tangential migration in all directions and over long distances, after reaching the cortex by dorsomedial tangential migration. The MDT migration in the MZ may disperse and intermix interneurons within the cortex, resulting in a balanced distribution of interneuron subtypes. [ABSTRACT FROM AUTHOR]

Neuronal migration is a prerequisite event for the establishment of highly ordered neuronal circuits in the developing brain. Here, we report Pax6-dependent alignment of the olfactory cortex neurons in the developing telencephalon. These neurons were generated in the dorsal part of telencephalon, migrated ventrally and stopped at the pallium-subpallium boundary (PSB). In Pax6 mutant rat embryos, however, these neurons invaded the ventral part of the telencephalon by crossing the PSB. Ephrin A5, one of the ligands for EphA receptors, was specifically expressed in the ventral part of the telencephalon, and its expression level was markedly reduced in the Pax6 mutant. Gain- and loss-of-function studies of ephrin A5 indicated that ephrin A5 plays an important role in the alignment of olfactory cortex neurons at the PSB. Our results suggest that Pax6-regulated ephrin A5 acts as a repulsive molecule for olfactory cortex neurons in the developing telencephalon. [ABSTRACT FROM AUTHOR]

Nuclei are aggregates of neurons distributed in the central nervous system and are fundamental functional units that share anatomical and physiological features. Despite their importance, the cellular basis that leads to nucleogenesis is only poorly understood. Using exo utero electroporation with an enhanced yellow fluorescent protein (EYFP) gene, we show that the precerebellar neurons derived from the lower rhombic lip (lRL) undergo multiple migration steps to form nuclei. After the unilateral transfer of EYFP to the lRL of embryonic day 12.5 mice, EYFP-labelled neurons migrate tangentially from the lRL in two distinct streams, one towards the ventral metencephalon and the other towards the ventral myelencephalon. These neurons cross the ventral midline and then become radially directed. Labelled neurons in the tangential migratory streams form contralateral clusters in the external cuneate nucleus (ECN) and lateral reticular nucleus (LRN) in the myelencephalon, and bilateral clusters in the pontine grey nucleus (PGN) and reticulotegmental nucleus (RTN) in the metencephalon. Before forming the clusters, EYFP-labelled neurons begin to migrate radially towards the ventricle in close apposition to nestin-positive radial fibres, and then they aggregate as they detach from the fibres. Inhibition of cadherin function in ECN and LRN progenitors caused ipsilateral formation of the ECN and LRN, implying that the transition of their migration from tangential to radial involves a cell-intrinsic mechanism. These observations suggest that nucleogenesis of precerebellar neurons is a result of multi-phasic migration, and that ventricle-directed radial glia-guided migration is a key step for nucleogenesis. [ABSTRACT FROM AUTHOR]