GAP junctional communication in brain secondary organizers.

Gap junctions (GJs) are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular weight metabolites between adjacent cells. They are formed by the apposition of two connexons belonging to adjacent cells. Each connexon is formed by six proteins, named connexins (Cxs). Current evidence suggests that gap junctions play an important part in ensuring normal embryo development. Mutations in connexin genes have been linked to a variety of human diseases, although the precise role and the cell biological mechanisms of their action remain almost unknown. Among the big family of Cxs, several are expressed in nervous tissue but just a few are expressed in the anterior neural tube of vertebrates. Many efforts have been made to elucidate the molecular bases of Cxs cell biology and how they influence the morphogenetic signal activity produced by brain signaling centers. These centers, orchestrated by transcription factors and morphogenes determine the axial patterning of the mammalian brain during its specification and regionalization. The present review revisits the findings of GJ composed by Cx43 and Cx36 in neural tube patterning and discuss Cx43 putative enrollment in the control of Fgf8 signal activity coming from the well known secondary organizer, the isthmic organizer.

Molecular events directing the patterning and specification of the cerebellum

The vertebrate brain is a remarkably complex anatomical structure which contains diverse subdivisions and neuronal subtypes with specific synaptic connections that contribute to the complexity of its function. The neural tube (the primordial brain) has to be progressively regionalized by means of precise control of the spatial and temporal arrangement of an orchestrated cocktail of genes. These will regulate inter- and intracellular signals driving a proper molecular patterning and specification of the distinct brain subdivisions, and thus will generate the structural basis of complexity and cellular diversity which characterize the brain. The present revision focuses on the main molecules involved during early development of the vertebrate cerebellum, the most rostral and dorsal structure of the hindbrain. We will survey the literature related to the early molecular mechanisms arising from the isthmus to pattern the caudal midbrain and rostral hindbrain primordia. The isthmus retains morphogenetic properties to further refining these subdivisions. Once the patterning of the cerebellar anlage is established, further molecular events (coming from the ventricular side and the rhombic lip) will specify the diverse neural cell population and the fine-tuning of the stereotyped morphology and layers of the cerebellum. Finally, we will discuss the combination of molecular genetics (gene expression pattern maps) and modern neuroanatomy (based on immunohistochemistry and highly sensitive neuroimaging), which have led to an increased interest in describing the neurodevelopment mechanisms underlying structural disorders and intellectual discapacities that we currently observe in congenital anomalies of the human cerebellum

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Cellular and molecular basis of cerebellar development.

Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.