Independent Genomic Control of Neuronal Number across Retinal Cell Types

Abstract

Summary The sizes of different neuronal populations within the central nervous system are precisely controlled, but whether neuronal number is coordinated between cell types is unknown. We examined the covariance structure of twelve different retinal cell types across thirty genetically distinct lines of mice, finding minimal co-variation when comparing synaptically-connected or developmentally-related cell types. Variation mapped to one or more genomic loci for each cell type, but rarely were these shared, indicating minimal genetic co-regulation of final number. Multiple genes, therefore, participate in the specification of the size of every population of retinal neuron, yet genetic variants work largely independent of one another during development to modulate those numbers, yielding substantial variability in the convergence ratios between pre- and post-synaptic populations. Density-dependent cellular interactions in the outer plexiform layer overcome this variability to ensure the formation of neuronal circuits that maintain constant retinal coverage and complete afferent sampling.

Sox2 Regulates Cholinergic Amacrine Cell Positioning and Dendritic Stratification in the Retina

“…This is further supported by the observation that the processes of the cholinergic amacrine cells in the INL in the Sox2-CKO retina are no longer immunopositive for the purinoceptor P2X2 (Kaneda et al, 2004;Fig. 7L).…”

“…The SNP Browser at GeneNetwork was used to query the presence of single nucleotide polymorphisms (SNPs) between the B6/J and A/J strains for the portion of the genome underlying each QTL of interest. This list was supplemented by a search for SNPs and short insertions or deletions (INDELs) using the query tools generated as part of the Mouse Genomes Project (Keane et al, 2011). Genes with variants in putative regulatory regions (3Ј-UTR, 5Ј-UTR, upstream, or downstream) or variants possibly altering protein function (e.g., missense or nonsense mutations) were identified using these two resources.…”

“…The subfamily of SoxB1 proteins are transcriptional activators that bind to DNA via their HMG-box domain. This binding is not particularly stable, however, and requires the additional binding of a coactivator to initiate transcriptional activation (Kamachi et al, 2000;Miyagi et al, 2009). The presence of two additional glycines in the B6/J protein may alter the stability of binding in the presence of such coactivators.…”

“…To test this hypothesis, cholinergic-specific Sox2 mutants (Sox-CKO mice) were generated by crossing mice expressing cre recombinase under the control of an endogenous ChAT promoter with floxedSox2 mice. ChAT expression begins as these cells coalesce in the inner retina, before the cholinergic amacrine cells have separated into two distinct populations (Kim et al, 2000), so the excision of Sox2 should occur before their relative positioning is established. Sox2-CKO mice lacked Sox2 protein expression in cholinergic neurons (Fig.…”

“…Early in development, cholinergic amacrine cells form a single stratum within the inner retina at the site of the future IPL (Prada et al, 1999;Kim et al, 2000), subsequently separating into two populations, with dendritic arbors arising from either the apical or basal side of the soma directed into the IPL (Stacy and Wong, 2003). Because cholinergic amacrine cells are generated over a period of days during retinal neurogenesis (Reese and Colello, 1992;Voinescu et al, 2009), they continue to migrate into these two cellular layers during the perinatal period, dispersing tangentially as they become inserted into the regular retinal mosaics forming therein (Galli-Resta et al, 1997).…”