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Originally published in Science Express on 5 September 2002
Science 25 October 2002:
Vol. 298. no. 5594, pp. 827 - 830
DOI: 10.1126/science.1075620
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Reports

Progression of Vertebrate Limb Development Through SHH-Mediated Counteraction of GLI3

Pascal te Welscher,1 Aimée Zuniga,1 Sanne Kuijper,2 Thijs Drenth,1 Hans J. Goedemans,1 Frits Meijlink,2 Rolf Zeller1*

Distal limb development and specification of digit identities in tetrapods are under the control of a mesenchymal organizer called the polarizing region. Sonic Hedgehog (SHH) is the morphogenetic signal produced by the polarizing region in the posterior limb bud. Ectopic anterior SHH signaling induces digit duplications and has been suspected as a major cause underlying congenital malformations that result in digit polydactyly. Here, we report that the polydactyly of Gli3-deficient mice arises independently of SHH signaling. Disruption of one or both Gli3 alleles in mouse embryos lacking Shh progressively restores limb distal development and digit formation. Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development.

1 Department of Developmental Biology, Faculty of Biology, Utrecht University, Padualaan 8, NL-3584 CH Utrecht, Netherlands.
2 Hubrecht Laboratorium, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.
*   To whom correspondence should be addressed. E-mail: R.Zeller{at}bio.uu.nl

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