PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration.

Chemokine receptor CXCR7 non-cell-autonomously controls pontine neuronal migration and nucleus formation.

Long distance tangential migration transports neurons from their birth places to distant destinations to be incorporated into neuronal circuits. How neuronal migration is guided during these long journeys is still not fully understood. We address this issue by studying the migration of pontine nucleus (PN) neurons in the mouse hindbrain.

Netrin-1 Derived from the Ventricular Zone, but not the Floor Plate, Directs Hindbrain Commissural Axons to the Ventral Midline.

Netrin-1 (Ntn1) emanating from the ventral midline has been thought to act as a long-range diffusible chemoattractant for commissural axons (CAs). However, CAs still grow towards the midline in the absence of the floor plate (FP), a glial structure occupying the midline. Here, using genetically loss-of-function approaches in mice, we show that Ntn1 derived from the ventricular zone (VZ), but not the FP, is crucial for CA guidance in the mouse hindbrain.

Distinct migratory behaviors of striosome and matrix cells underlying the mosaic formation in the developing striatum.

The striatum, the largest nucleus of the basal ganglia controlling motor and cognitive functions, can be characterized by a labyrinthine mosaic organization of striosome/matrix compartments. It is unclear how striosome/matrix mosaic formation is spatially and temporally controlled at the cellular level during striatal development. Here, by combining in vivo electroporation and brain slice cultures, we set up a prospective experimental system in which we differentially labeled striosome and matrix cells from the time of birth and followed their distributions and migratory behaviors.

In vivo imaging of cortical interneurons migrating in the intermediate/subventricular zones.

We developed an imaging system that enables migrating cortical interneurons (CIs) through the lower intermediate zone/subventricular zone (IZ/SVZ) in mouse embryos. CIs were labeled by in utero electroporation performed at embryonic day (E) 11.5 and were observed, through the skull of living embryos, detached from the dam with the umbilical cord remain attached.

Evidence That the Laminar Fate of LGE/CGE-Derived Neocortical Interneurons Is Dependent on Their Progenitor Domains.

Unlabelled: Neocortical interneurons show tremendous diversity in terms of their neurochemical marker expressions, morphology, electrophysiological properties, and laminar fate. Allocation of interneurons to their appropriate regions and layers in the neocortex is thought to play important roles for the emergence of higher functions of the neocortex. Neocortical interneurons mainly originate from the medial ganglionic eminence (MGE) and the caudal ganglionic eminence (CGE).

Association of astrocytes with neurons and astrocytes derived from distinct progenitor domains in the subpallium.

Astrocytes play pivotal roles in metabolism and homeostasis as well as in neural development and function in a manner thought to depend on their region-specific diversity. In the mouse spinal cord, astrocytes and neurons, which are derived from a common progenitor domain (PD) and controlled by common PD-specific transcription factors, migrate radially and share their final positions. However, whether astrocytes can only interact with neurons from common PDs in the brain remains unknown.

Chemokine Signaling Controls Integrity of Radial Glial Scaffold in Developing Spinal Cord and Consequential Proper Position of Boundary Cap Cells.

Radial glial cells are the neural progenitors of the developing CNS and have long radial processes that guide radially migrating neurons. The integrity of the radial glial scaffold, in particular proper adhesion between the endfeet of radial processes and the pial basement membrane (BM), is important for the cellular organization of the CNS, as indicated by evidence emerging from the developing cortex. However, the mechanisms underlying the maintenance of radial glial scaffold integrity during development, when the neuroepithelium rapidly expands, are still poorly understood.

Specific labeling of climbing fibers shows early synaptic interactions with immature Purkinje cells in the prenatal cerebellum.

During development, growing axons must locate target cells to form synapses. This is not easy, since target cells are also growing and even actively migrating. In some brain regions, such axons have been reported to wait for the timing when target cells become mature, without invading their target region.

Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons.

The calcium ion regulates many aspects of neuronal migration, which is an indispensable process in the development of the nervous system. Calmodulin (CaM) is a multifunctional calcium ion sensor that transduces much of the signal. To better understand the role of Ca(2+)-CaM in neuronal migration, we investigated mouse precerebellar neurons (PCNs), which undergo stereotyped, long-distance migration to reach their final position in the developing hindbrain.

Evidence that dendritic mitochondria negatively regulate dendritic branching in pyramidal neurons in the neocortex.

The precise branching patterns of dendritic arbors have a profound impact on information processing in individual neurons and the brain. These patterns are established by positive and negative regulation of the dendritic branching. Although the mechanisms for positive regulation have been extensively investigated, little is known about those for negative regulation.

N-cadherin sustains motility and polarity of future cortical interneurons during tangential migration.

In the developing brain, cortical GABAergic interneurons migrate long distances from the medial ganglionic eminence (MGE) in which they are generated, to the cortex in which they settle. MGE cells express the cell adhesion molecule N-cadherin, a homophilic cell-cell adhesion molecule that regulates numerous steps of brain development, from neuroepithelium morphogenesis to synapse formation. N-cadherin is also expressed in embryonic territories crossed by MGE cells during their migration.

Development of cerebellar neurons and glias revealed by in utero electroporation: Golgi-like labeling of cerebellar neurons and glias.

Cerebellar cortical functions rely on precisely arranged cytoarchitectures composed of several distinct types of neurons and glias. Studies have indicated that cerebellar excitatory and inhibitory neurons have distinct spatial origins, the upper rhombic lip (uRL) and ventricular zone (VZ), respectively, and that different types of neurons have different birthdates. However, the spatiotemporal relationship between uRL/VZ progenitors and their final phenotype remains poorly understood due to technical limitations.

Role of neuropilin-2 in the ipsilateral growth of midbrain dopaminergic axons.

Axonal projections in the CNS can be categorized as either crossed or uncrossed. Crossing and uncrossing of axons has been explained by attractive and repulsive molecules like Netrin-1 and Slits, which are secreted by midline structures. However, uncrossed projections can be established even in double knockout mice of slit1 and slit2 or of roundabout1 (robo1) and robo2, two receptors for Slits.

Dynamics of the leading process, nucleus, and Golgi apparatus of migrating cortical interneurons in living mouse embryos.

Precisely arranged cytoarchitectures such as layers and nuclei depend on neuronal migration, of which many in vitro studies have revealed the mode and underlying mechanisms. However, how neuronal migration is achieved in vivo remains unknown. Here we established an imaging system that allows direct visualization of cortical interneuron migration in living mouse embryos.

Chemokine CXCL12 and its receptors in the developing central nervous system: emerging themes and future perspectives.

Homeostatic chemokine CXCL12 (also known as SDF-1) and its receptor CXCR4 are indispensable for the normal development of the nervous system. This chemokine system plays a plethora of functions in numerous neural developmental processes, from which the underlying molecular and cellular mechanisms are beginning to be unravelled. Recent identification of CXCR7 as a second receptor for CXCL12 provides opportunities to gain deeper insights into how CXCL12 operates in the nervous system.

Intrinsic and extrinsic mechanisms control the termination of cortical interneuron migration.

During development, neurons migrate from their site of origin to their final destinations. Upon reaching this destination, the termination of their migration is crucial for building functional architectures such as laminated structures and nuclei. How this termination is regulated, however, is not clear.

Formation of axon-dendrite polarity in situ: initiation of axons from polarized and non-polarized cells.

Neurons are polarized cells that extend a single axon and several dendrites. Historically, how neurons establish their axon-dendrite polarity has been extensively studied using dissociated hippocampal cells in culture. Although such studies have identified the cellular and molecular mechanisms underlying axon-dendrite polarization, the conclusions have been limited to in vitro conditions.

Temporally- and spatially regulated generation of distinct descendants by sonic hedgehog-expressing progenitors in the forebrain.

The generation of distinct neural subtypes depends on the activities of cell-extrinsic and -intrinsic factors during the development of the vertebrate CNS. Previous studies have provided a molecular basis for how neural progenitors are patterned and generate distinct descendants that are spatially and temporally regulated by inductive signals secreted by polarized sources. However, it still remains unknown how the generation of neural descendants by progenitors located at polarized sources of inductive signals is controlled.

CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons.

Cortical GABAergic interneurons are divided into various subtypes, with each subtype contributing to rich variety and fine details of inhibition. Despite the functional importance of each interneuron subtype, the molecular mechanisms that contribute to sorting them to their appropriate positions within the cortex remain unclear. Here, we show that the chemokine receptor CXCR4 regulates the regional and layer-specific distribution of interneuron subtypes.