Proneural genes and cerebellar neurogenesis in the ventricular zone and upper rhombic lip

Abstract

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 morphogens secreted by the rhombic lip and roof plate, and leads to the formation of two main neurogenetic centers, the upper rhombic lip and 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 proneural gene, acts as a master gene in granule cell differentiation, survival, and dendrite formation. Ascl1 participates in GABA interneuron and cerebellar nuclei neurons 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 role, if any, in cerebellar neurogenesis.