Abstract
Granule cells (GCs) are the most numerous cell type in the cerebellum and indeed, in the brain: at least 99% of all cerebellar neurons are granule cells. In this review article, we first consider the formation of the upper rhombic lip, from which all granule cell precursors arise, and the way by which the upper rhombic lip generates the external granular layer, a secondary germinal epithelium that serves to amplify the upper rhombic lip precursors. Next, we review the mechanisms by which postmitotic granule cells are generated in the external granular layer and migrate radially to settle in the granular layer. In addition, we review the evidence that far from being a homogeneous population, granule cells come in multiple phenotypes with distinct topographical distributions and consider ways in which the heterogeneity of granule cells might arise during development.
Highlights
We address how granule cells (GCs) develop: their origins in the upper rhombic lip (URL: known as the anterior or rostral rhombic lip) and the elaborate migrations and amplifications that lead Granule Cell (GC) to become the most populous neurons in the brain, and secondly the embryological origins of granular layer (GL) heterogeneity
Each transverse zone is further subdivided into parasagittal stripes, which can be identified by molecular markers; phospholipase Cβ4 (Sarna et al, 2006); heat shock protein 25 (HSP25; Armstrong et al, 2000) and the effects of mutations [rostral cerebellar malformation Eisenman and Brothers, 1998; e.g., cerebellar deficient folia Beierbach et al, 2001; Niemann Pick disease type C1 (NPC1) Sarna and Hawkes, 2003]
Does Atoh1 label a population of regionspecific stem cells or a heterogeneous pool of committed progenitors? In that case, do these committed progenitors originate from ‘‘universal’’ Sox2+ apical progenitors or an, as yet undiscovered, URL-specific, asymmetrically dividing stem cell restricted to glutamatergic fates? And if so, what marks this putative stem cell? An attractive candidate is the Wls gene, which labels apical progenitors negative for Atoh1 (Yeung et al, 2014)
Summary
Given the space constraints we do not review synaptogenesis and circuit formation; recent reviews may be found in Leto et al (2015) and Lackey et al (2018) This aspect has been covered in several excellent reviews (inter alia Yuzaki, 2011) and in recent research articles that suggest there is much to find out about this critical process (Toledo et al, 2019; Yang et al, 2019; Table 1). The “Chromosome” column lists on which chromosome each gene is located. The “Start” and “End” columns list in base pairs along a chromosome at which a gene begins and ends, respectively. Under the “Mouse Phenotypes” heading, a list of nervous system-related phenotypes is provided, including those that are specific to the cerebellum
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