Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

Abstract

The morphogen sonic hedgehog (Shh) plays a crucial role in development of the CNS, including the neural retina. Suppressor of fused (Sufu) has been recently identified as a critical regulator of Hh signaling in mammals. However, the precise roles that Sufu plays in the regulation of proliferation and cell-fate decisions in neural progenitors is unknown. Here, we have addressed these questions by conditionally deleting Sufu in mouse multipotent retinal progenitor cells (RPCs). Sufu deletion in RPCs results in transient increases in Hh activity and proliferation followed by developmentally premature cell-cycle exit. Importantly, we demonstrate a novel role for Sufu in the maintenance of multipotency in RPCs. Sufu-null RPCs downregulate transcription factors required to specify or maintain RPC identity (Rax, Vsx2) and multipotency (Pax6) but continue to express the neural progenitor marker Sox2. These cells fail to express retinal lineage-specific transcription factors, such as Math5, and adopt an amacrine or horizontal cell fate at the expense of all other classes of retinal neurons. Genetic elimination of Gli2 in Sufu-null RPCs attenuates Hh pathway activity and restores multipotency in neural progenitors. These data provide novel evidence that Sufu-mediated antagonism of Hh/Gli2 signaling is required to maintain RPC multipotency and identity.

LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli

“…The SHH pathway is the target of receptor (dys)function, as other morphogen pathways are not altered (e.g., Ihh and Bmp4) (Figures 3A and S3B) or decreased secondarily as shown by downregulation of WNT activity by SAG ( Figure 5D). Enhanced RPC proliferation as a consequence of increased Hh signaling is also seen in mice heterozygous for the Ptch1 gene defect (Moshiri and Reh, 2004) or in animals lacking Sufu, an inhibitor of the SHH pathway (Cwinn et al, 2011). In contrast, a WNT signaling defect in mice lacking b-catenin in the retina causes a decrease, rather than an increase, in the progenitor cell pool (Liu et al, 2007).…”

Extramacrochaetae imposes order on the Drosophila eye by refining the activity of the Hedgehog signaling gradient

“…Our own results support these findings, as expression of Su(fu) reduces the ability of Ci ACT to activate a Ci-dependent luciferase reporter. Within the mouse eye, loss of Su(fu) leads to an increase in Hh signaling which in turn results in retinal hyperplasia, late onset premature exit from the cell cycle, and an increase in the number of horizontal and amacrine cells at the expense of other cell types (Cwinn et al, 2011). By contrast, Su(fu) does not appear to be a rate-limiting component of the Hh pathway in Drosophila and, as such, null mutants are completely viable and have normally constructed eyes (Préat, 1992;Shi et al, 2011;Zhou and Kalderon, 2011).…”

The role of homeobox genes in retinal development and disease

“…2) while centrally localized RPC require Pax6 to retain multipotency (Oron-Karni et al, 2008). Recently, Pax6 was identified as being downstream of suppressor-of-fused (Sufu), a negative regulator of the Hedgehog signaling pathway (Cwinn et al, 2011;Svard et al, 2006;Varjosalo et al, 2006). Conditional loss of Sufu in the proximal retina results in Pax6 down-regulation and phenocopies the Pax6 conditional knockout described above Pax6 is required to maintain multipotency of RPC and restrict Crx expression in peripheral RPC.…”

“…Up-regulation of Crx also positively regulates its own expression. (Cwinn et al, 2011). In addition to its role in the neural retina, Pax6 is required for lens development.…”