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Published online January 5, 2009
doi:10.1083/jcb.200805155
The Journal of Cell Biology, Vol. 184, No. 1, 101-112
The Rockefeller University Press, 0021-9525 $30.00
© 2009 Wall et al.
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Article

Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity



Dana S. Wall1,2, Alan J. Mears1,3,4, Brian McNeill1,2, Chantal Mazerolle1, Sherry Thurig1, Yaping Wang1, Ryoichiro Kageyama5, and Valerie A. Wallace1,2,4

1 Vision Program, Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada
2 Department of Biochemistry, Microbiology and Immunology; 3 Department of Cellular and Molecular Medicine; and 4 Department of Ophthalmology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
5 Institute for Virus Research, Kyoto University and Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Kyoto 606-8507, Japan

Correspondence to Valerie A. Wallace: vwallace{at}ohri.ca

Sonic hedgehog (Shh) is an indispensable, extrinsic cue that regulates progenitor and stem cell behavior in the developing and adult mammalian central nervous system. Here, we investigate the link between the Shh signaling pathway and Hes1, a classical Notch target. We show that Shh-driven stabilization of Hes1 is independent of Notch signaling and requires the Shh effector Gli2. We identify Gli2 as a primary mediator of this response by showing that Gli2 is required for Hh (Hedgehog)-dependent up-regulation of Hes1. We also show using chromatin immunoprecipitation that Gli2 binds to the Hes1 promoter, which suggests that Hes1 is a Hh-dependent direct target of Gli2 signaling. Finally, we show that Shh stimulation of progenitor proliferation and cell diversification requires Gli2 and Hes1 activity. This paper is the first demonstration of the mechanistic and functional link between Shh, Gli, and Hes1 in the regulation of progenitor cell behavior.

Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; CNS, central nervous system; CRALBP, cellular retinaldehyde-binding protein; DAPT, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; DIV, days in vitro; E, embryonic day; Hh, Hedgehog; IHC, immunohistochemistry; ISH, in situ hybridization; P, postnatal day; Ptch, Patched; RGC, retinal ganglion cell; RPC, retinal progenitor cell; RT-qPCR, quantitative RT-PCR; Shh, Sonic hedgehog; Smo, Smoothened.

© 2009 Wall et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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