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The Journal of Neuroscience, May 27, 2009, 29(21):6932-6944; doi:10.1523/JNEUROSCI.0289-09.2009

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Development/Plasticity/Repair
Distinct Effects of Hedgehog Signaling on Neuronal Fate Specification and Cell Cycle Progression in the Embryonic Mouse Retina

Kiyo Sakagami,¹ Lin Gan,³ and Xian-Jie Yang^1,2

¹Jules Stein Eye Institute and Department of Ophthalmology, and ²Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, and ³Department of Ophthalmology, University of Rochester, Rochester, New York 14642

Correspondence should be addressed to Xian-Jie Yang, Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095. Email: yang{at}jsei.ucla.edu

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 G₁/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 G₁/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.

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Received Jan. 17, 2009; revised March 31, 2009; accepted April 22, 2009.

Correspondence should be addressed to Xian-Jie Yang, Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095. Email: yang{at}jsei.ucla.edu

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