title: 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.
authors: Vision Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
authors: Matt A
authors: MA
authors: Cwinn
authors: Chantal
authors: C
authors: Mazerolle
authors: Brian
authors: B
authors: McNeill
authors: Randy
authors: R
authors: Ringuette
authors: Sherry
authors: S
authors: Thurig
authors: Chi-chung
authors: CC
authors: Hui
authors: Valerie A
authors: VA
authors: Wallace
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011897:Random Allocation; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse