A gene network downstream of transcription factor Math5 regulates retinal progenitor cell competence and ganglion cell fate

Abstract

Math5, a mouse homolog of the Drosophila proneural bHLH transcription factor Atonal, is essential in the developing retina to establish retinal progenitor cell competence for a ganglion cell fate. Elucidating the mechanisms by which Math5 influences progenitor cell competence is crucial for understanding how specification of neuronal cell fate occurs in the retina and it requires knowledge of the downstream target genes that depend on Math5 for their expression. To date, only a handful of genes downstream of Math5 have been identified. To better define the gene network operating downstream of Math5, we used custom-designed microarrays to examine the changes in embryonic retinal gene expression caused by deletion of math5. We identified 270 Math5-dependent genes, including those that were expressed specifically either in progenitor cells or differentiated ganglion cells. The ganglion cell-specific genes included both Brn3b-dependent and Brn3b-independent genes, indicating that Math5 regulates distinct branches of the gene network responsible for retinal ganglion cell differentiation. In math5-null progenitor cells, there was an up-regulation of the proneural genes math3, neuroD, and ngn2, indicating that Math5 suppresses the production of other cell types in addition to promoting retinal ganglion cell formation. The promoter regions of many Math5-dependent genes contained binding sites for REST/NRSF, suggesting that release from general repression in retinal progenitor cells is required for ganglion cell-specific gene activation. The identification of multiple roles for Math5 provides new insights into the gene network that defines progenitor cell competence in the embryonic retina.

Transcription Factors SOX4 and SOX11 Function Redundantly to Regulate the Development of Mouse Retinal Ganglion Cells

“…2, B and C). To remove Sox11 in the retina, we used Six3-cre mice, which express Cre recombinase in the eye field and ventral forebrain starting at E9 to E9.5 (24,29). Homozygous Sox11 loxP/loxP mice were bred with Six3-cre mice to yield retina-specific Sox11 CKO (Sox11 loxP/loxP ; Six3-cre) mice.…”

“…Based on the spatiotemporal expression pattern of Sox4 and Sox11 in the NBL as well as in the GCL during early retinogen- esis, we hypothesized that Sox4 and Sox11 are the genes promoting RGC fate commitment. Expressions of Sox4 and Sox11 have been shown to be down-regulated by ϳ30 and 50% in Math5 Ϫ/Ϫ retinas at E14.5 in comparison to control using microarray analysis (29), however, no further study was conducted to confirm the finding. Our analysis using Math5-null mutant provides direct evidence proving that loss of Math5 greatly impairs the expression of both SoxC genes in the GCL.…”

SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling

“…Brn3b is a prominent RGC regulatory gene whose activation heralds phenotypic differentiation of RGC precursors through subsequent activation of downstream target genes such as Shh (10,52). We were interested in knowing whether Brm regulated RGC differentiation by facilitating the activation of Brn3b and Shh.…”

A cascade of irx1a and irx2a controls shh expression during retinogenesis

“…In the mouse, gene-encoded secreted molecules, including Shh, GDF8, and VEGFa, were all down-regulated in Math5 null retina (Mu et al, 2005). In the zebrafish, since the shh wave propagates normally in the INL but not in the GCL of ath5 mutant retina, which completely lacks RGCs (Kay et al, 2001), the wave of shh expression in the INL is independent of ath5 and shh expression in the GCL (Shkumatava et al, 2004).…”