Distinct effects of Hedgehog signaling on neuronal fate specification and cell cycle progression in the embryonic mouse retina.
Cell-extrinsic signals can profoundly influence the production of various neurons from common progenitors. Yet mechanisms by which extrinsic signals coordinate progenitor cell proliferation, cell cycle exit, and cell fate choices are not well understood. Here, we address whether Hedgehog (Hh) signals independently regulate progenitor proliferation and neuronal fate decisions in the embryonic mouse retina. Conditional ablation of the essential Hh signaling component Smoothened (Smo) in proliferating progenitors, rather than in nascent postmitotic neurons, leads to a dramatic increase of retinal ganglion cells (RGCs) and a mild increase of cone photoreceptor precursors without significantly affecting other early-born neuronal cell types. In addition, Smo-deficient progenitors exhibit aberrant expression of cell cycle regulators and delayed G(1)/S transition, especially during the late embryonic stages, resulting in a reduced progenitor pool by birth. Deficiency in Smo function also causes reduced expression of the basic helix-loop-helix transcription repressor Hes1 and preferential elevation of the proneural gene Math5. In Smo and Math5 double knock-out mutants, the enhanced RGC production observed in Smo-deficient retinas is abolished, whereas defects in the G(1)/S transition persist, suggesting that Math5 mediates the Hh effect on neuronal fate specification but not on cell proliferation. These findings demonstrate that Hh signals regulate progenitor pool expansion primarily by promoting cell cycle progression and influence cell cycle exit and neuronal fates by controlling specific proneural genes. Together, these distinct cellular effects of Hh signaling in neural progenitor cells coordinate a balanced production of diverse neuronal cell types.
Sakagami
Kiyo
K
Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Gan
Lin
L
Yang
Xian-Jie
XJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000145:classification / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency; D012160:Retina / Q000166:cytology* / Q000196:embryology; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000072086:Smoothened Receptor; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D014157:Transcription Factors; C117638:Atoh7 protein, mouse; C491022:Smo protein, mouse; C088975:Vsx2 protein, mouse