'Suppressor of fused' antagonizes hedgehog signaling and is required to maintain retinal progenitor cell identity and multipotency

Abstract

The mature retina consists of six neuronal and one glial cell type that are derived from a pool of mulipotent progenitor cells (RPC). The decision to remain as a multipotent progenitor or to specify a particular retinal cell lineage and differentiate are governed by cell intrinsic and extrinsic factors. Sonic hedgehog (Shh) is a secreted lipoprotein that is motigenic for RPCs and influences cell fate decisions. Suppressor of fused (Sufu) is an intracellular antagonist of the pathway; however, its role in regulating Shh signaling and influencing cell fate decisions in RPCs are unknown. Here, I demonstrate that Sufu antagonizes the Hh pathway in RPCs both in vitro and in vivo. Surprisingly, Sufu was required to maintain early RPC identity and multipotency. Conditional deletion of Sufu in early RPCs resulted in the down-regulation of transcription factors required to maintain RPC identity and multipotency as well as transcription factors required to specify all seven retinal cell types.Sufu-null RPCs were incapable of differentiating into the normal complement of retinal cell types and instead differentiated into restricted subsets of interneurons. These data demonstrate that Sufu antagonizes the Hh pathway in RPCs and provides novel evidence that Sufu is required for proper progenitor cell behavior.