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The cerebellar primordium arises between embryonic days 8.5 and 9.5 from dorsal rhombomere 1, adjacent to the fourth ventricle. Cerebellar patterning requires the concerted action of several morphogens secreted by the rhombic lip and roof plate and leads to the formation of two main neurogenic centers, the upper rhombic lip and the ventricular zone, from which glutamatergic and GABAergic neurons arise, respectively. These territories contain gene expression microdomains that are partially overlapping and, among others, express proneural genes. This gene family is tightly conserved in evolution and encodes basic helix- loop-helix transcription factors implicated in many neurogenetic events, ranging from cell fate specification to terminal differentiation of a variety of neuronal types across the embryonic nervous system. The present paper deals with the established or suggested roles of proneural genes in cerebellar neurogenesis. Of the proneural genes examined in this chapter, Atoh1 plays a quintessential role in the specification and development of granule cells and other cerebellar glutamatergic neurons. Besides playing key roles at early stages in these early developmental events, Atoh1 is a key player in the clonal expansion of GC progenitors of the external granule layer. NeuroD , formerly regarded as a pro- neural gene, acts as a master gene in granule cell differentiation, survival, and dendrite formation. Ascl1 participates in GABA interneuron and cerebellar nuclei neuron generation and suppresses astrogliogenesis. Conversely, little is known to date about the role(s) of Neurog1 and Neurog2 in cerebellar neurogenesis, and a combination of loss- and gain-of-function studies is required to elucidate their contribution to cerebellar neurogenesis.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humeroperoneal dystrophy associated with cardiomyopathy that is distinct from the Duchenne and Becker forms of X-linked muscular dystrophy. Linkage analysis has assigned EDMD to the terminal region of the human X chromosome long arm. We report here further linkage analysis in two multigenerational EDMD families using seven Xq28 marker loci. Cumulative lod scores suggest that EDMD is approximately 2 cM from DXS52 (lod = 15.67) and very close to the factor VIII (F8C) and the red/green color pigment (R/GCP) loci, with respective lod scores of 9.62 and 10.77, without a single recombinant. Several recombinations between EDMD and three proximal Xq28 markers suggest that the EDMD gene is located in distal Xq28. Multipoint linkage analysis indicates that the odds are 2,000:1 that EDMD lies distal to DXS305. These data substantially refine the ability to perform accurate carrier detection, prenatal diagnosis, and the presymptomatic diagnosis of at-risk males for EDMD by linkage analysis. The positioning of the EDMD locus close to the loci for F8C and R/GCP will assist in future efforts to identify and isolate the disease gene.

Neuroendocrine control of physiological functions needs a complex developmental organisation of the hypothalamic parvicellular neurons, which synthesise and release hypophysiotropic hormones. Among the hypothalamic neuroendocrine cells, Gonadotropin-releasing hormone (GnRH) neurons represent a unique class; they are generated in the olfactory placode and, during embryonic life, migrate to the septo/hypothalamic region along terminal and vomeronasal nerves. At this level GnRH neurons undergo terminal differentiation and start to release GnRH to modulate the secretion of pituitary gonadotropins. All these steps are under the strict control of several developmental cues and their defect might represent a cause of clinical disorders. A number of factors have been proposed to be involved in the migration of GnRH neurons, but their role is still unclear. By using gene knockout techniques it has been found that mice carrying a targeted deletion of Ebf2 gene, a component of Olf/Ebf bHLH transcription factors, show a defective migration of GnRH neurons, providing the first evidence of a mouse model of such defect. Since the investigation of GnRH neurons is hindered by their peculiar anatomical distribution, other studies has been forwarded by the availability of immortalized GnRH-expressing neurons (GN11 cells) that retain a strong chemomigratory response "in vitro". Among the factors analysed, we found that hepatocyte growth factor/scatter factor (HGF/SF) and vascular endothelial growth factor (VEGF) induce specific chemotaxis of GN 11 neurons, suggesting that migratory signals can arise from nasal mesenchyme and from the concomitant vasculogenesis. Finally, anosmin-1 (the product of the gene responsible of the X-linked form of Kallmann's disease) was found to induce a significant chemotactic response of GN11 cells, confirming a permissive/instructive role of KAL1 gene product in the migratory behaviour of GnRH neurons. In conclusion, the migration of the GnRH neurons appears to be a complex process, which involves the interplay of multiple molecular cues. These studies may provide new insights on the etiopathogenesis of the large proportion of reproductive dysfunctions that affect humans and could provide novel insights on common biochemical events controlling neuronal development and migration.