Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina

Abstract

The timing of cell cycle exit and temporal changes in the developmental competence of precursor cells are key components for the establishment of the normal complement of cell types in the mammalian retina. The identity of cell extrinsic cues that control these processes is largely unknown. We showed previously in mouse retina that sonic hedgehog (Shh) signalling from retinal ganglion cells (RGCs) to retinal precursor cells (RPC) is required for the establishment of normal retinal organization. Here, we show that conditional ablation of Shh expression in the peripheral mouse results in a depletion of the RPC pool, owing to precocious cell-cycle exit and neuronal differentiation. These changes were correlated with the downregulation of cyclin D1 and Hes1 gene expression. Shh inactivation also results in an increase in RGC number owing to a bias of RPC towards RGC production. In contrast to zebrafish, where Shh signalling drives cell cycle exit and RGC development, our findings indicate that in the mouse retina Shh signalling is required to maintain RPC proliferation and to control the timing of RGC development.

Nuclear migration during retinal development

“…This could be accomplished by differential activation of cell surface receptors associated with the cell body and/or differential effects on gene regulation within the nucleus. Potential neurogenicmodulating factors include retinal ganglion cell secreted Sonic hedgehog (Shh) and Gliaderived Factor 11 (Gdf11) (Locker et al, 2006;Wang et al, 2005;Kim et al, 2005). Alternatively, differences in nuclear position and the organelles associated with the nucleus may enable differential shuttling/post-translational modifications of fate-determinants, which then affect neurogenesis and mediate differentiation among progenitors cells.…”

Fibroblast growth factor–hedgehog interdependence during retina regeneration

“…Other examples of Hh regulating proliferation and cell death are illustrated in studies on different types of cancer (Qualtrough et al, 2004;Romer et al, 2004;Sanchez et al, 2004;Sanchez and Ruiz i Altaba, 2005). Likewise, Hh signaling is also involved in progenitor cell proliferation and survival during eye development in several different organisms (Stenkamp et al, 2002, and reviewed in Amato et al, 2004Wang et al, 2005). Shh has also been implicated in controlling proliferation during regenerative processes.…”

“…For example, a role for Hh signaling in progenitor cell maintenance has been shown in the developing retina where conditional ablation of Shh in mouse retinas led to a reduction of the retina progenitor (precursor) cell pool (Wang et al, 2005). One of the best examples of Hh signaling specifying and maintaining the identity of neural progenitors takes place during neurogenesis where Shh regulates progenitor cell identity and neuronal fate in the ventral neural tube and developing spinal cord (Ericson et al, 1996(Ericson et al, , 1997Briscoe et al, 2000;Agius et al, 2004).…”

In vivo evidence for unbiased ikaros retinal lineages using an ikaros‐cre mouse line driving clonal recombination

“…Moreover, when RPCs are plated at clonal density, they generate clones that are of similar size and composition as clones that develop in situ, and the general order of cell type production in the population is reproduced (Cayouette et al, 2003). Although feedback inhibition signals from the environment can clearly influence the proportion of specific cell types produced (Reh and Tully, 1986;Reh, 1992;Waid and McLoon, 1998;Wang et al, 2005), even in clonal cultures, these results are consistent with a model in which RPCs do not require specific instructive environmental signals for proper cell fate specification, but rather depend on cell intrinsic cues acting to bias their developmental potential over time (Cayouette et al, 2006;Gomes et al, 2011).…”