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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.03.021 Byline: Nicole M. Collette (a)(b), Damian C. Genetos (c), Deepa Murugesh (a)(b), Richard M. Harland (b), Gabriela G. Loots (a)(b) Keywords: WNT signaling; SOST; Sclerostin; Shh; Limb formation Abstract: SOST is a negative regulator of bone formation, and mutations in human SOST are responsible for sclerosteosis. In addition to high bone mass, sclerosteosis patients occasionally display hand defects, suggesting that SOST may function embryonically. Here we report that overexpression of SOST leads to loss of posterior structures of the zeugopod and autopod by perturbing anterior-posterior and proximal-distal signaling centers in the developing limb. Mutant mice that overexpress SOST in combination with Grem1 and Lrp6 mutations display more severe limb defects than single mutants alone, while Sost.sup.- .sup./ .sup.- significantly rescues the Lrp6.sup.- .sup./ .sup.- skeletal phenotype, signifying that SOST gain-of-function impairs limb patterning by inhibiting the WNT signaling through LRP5/6. Author Affiliation: (a) Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA (b) Department of Molecular and Cell Biology, Division of Genetics, Genomics, and Development, and Center for Integrative Genomics, University of California, Berkeley, CA 94720-3204, USA (c) Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA Article History: Received 19 June 2009; Revised 18 March 2010; Accepted 22 March 2010