Ptf1a determines horizontal and amacrine cell fates during mouse retinal development

Abstract

The vertebrate neural retina comprises six classes of neurons and one class of glial cells, all derived from a population of multipotent progenitors. There is little information on the molecular mechanisms governing the specification of cell type identity from multipotent progenitors in the developing retina. We report that Ptf1a, a basic-helix-loop-helix (bHLH) transcription factor, is transiently expressed by post-mitotic precursors in the developing mouse retina. Recombination-based lineage tracing analysis in vivo revealed that Ptf1a expression marks retinal precursors with competence to exclusively produce horizontal and amacrine neurons. Inactivation of Ptf1a leads to a fate-switch in these precursors that causes them to adopt a ganglion cell fate. This misspecification of neurons results in a complete loss of horizontal cells, a profound decrease of amacrine cells and an increase in ganglion cells. Furthermore, we identify Ptf1a as a primary downstream target for Foxn4, a forkhead transcription factor involved in the genesis of horizontal and amacrine neurons. These data, together with the previous findings on Foxn4, provide a model in which the Foxn4-Ptf1a pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine cell fates.

Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression

“…A similar finding has been reported in the retina (15). Altogether, it is likely that the Ptf1a gene may control the expression of key regulatory genes in certain GABAergic phenotypes (such as PCs and interneurons in the cerebellum and spinal cord), although we can only speculate as to which genes are targeted by Ptf1a.…”

“…Ptf1a is also required for the generation of dorsal horn GABAergic interneurons in the spinal cord, and, in its absence, Ptf1a-derived cells adopt a glutamatergic phenotype (14). A recent study in the retina shows that inactivation of Ptf1a leads to a fate switch in horizontal and amacrine cell precursors that causes them to adopt a ganglion cell fate (15). We have examined the role of Ptf1a in the development of the cerebellum by analyzing the phenotype of mice lacking the complete Ptf1a coding sequence (Ptf1a Cre knockin).…”

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

“…6G-L) (Qiu et al, 2008), consistent with the abnormal differentiation of most amacrine cells in this layer of the mutant retina. It has been shown that Neurod1, Math3 and Ptf1a are required for specifying amacrine cells and Bhlhb5 and Nr4a2 for differentiation of GABAergic amacrine cells (Feng et al, 2006;Fujitani et al, 2006;Inoue et al, 2002;Jiang and Xiang, 2009;Nakhai et al, 2007). Similarly, there was a significant increase in expression of Prox1, Ptf1a, Lim1 and Ngn2, all transcription factor genes involved in horizontal cell development (Akagi et al, 2004;Dyer et al, 2003;Fujitani et al, 2006;Liu et al, 2000b;Nakhai et al, 2007;Poche et al, 2007), within the INBL of Pou4f2 null retinas (Fig.…”

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

“…Nevertheless, deletion of both Oc1 and Oc2 together leads to complete failure of HC genesis, confirming the redundancy of these two factors in the HC lineage. Two major regulators involved in the HC fate are FoxN4 and Ptf1a, with FoxN4 being upstream (29,30). We recently showed that Oc1 functions together with Ptf1a at the same level in the regulatory hierarchy to promote the HC fate and inhibit the amacrine cell fate (14).…”