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Here, we show that inactivation of <jats:italic>Sfrp2<\/jats:italic> results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft\u2010tissue syndactyly of the hindlimb. The brachydactyly is caused by decreased chondrocyte proliferation and delayed differentiation in distal limb chondrogenic elements. These data suggest that <jats:italic>Sfrp2<\/jats:italic> can regulate both chondrogenesis and regression of interdigital mesenchyme in distal limb. <jats:italic>Sfrp2<\/jats:italic> can also repress canonical Wnt signaling by <jats:italic>Wnt1<\/jats:italic>, <jats:italic>Wnt9a<\/jats:italic>, and <jats:italic>Wnt4<\/jats:italic> in vitro. <jats:italic>Sfrp2<\/jats:italic>\u2212\/\u2212 and TOPGAL\/<jats:italic>Sfrp2<\/jats:italic>\u2212\/\u2212 mice have a mild increase in beta\u2010catenin and beta\u2010galactosidase staining, respectively, in some phalangeal elements. This however does not exclude a potential concurrent effect on non\u2010canonical Wnt signaling in the growth plate. In combination with what is known about BMP and Wnt signaling in human brachydactylies, our data establish a critical role for <jats:italic>Sfrp2<\/jats:italic> in proper distal limb formation and suggest <jats:italic>SFPR2<\/jats:italic> could be a novel candidate gene for human brachy\u2013syndactyly defects. J. Cell. Physiol. 217: 127\u2013137, 2008. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.21483","type":"journal-article","created":{"date-parts":[[2008,4,29]],"date-time":"2008-04-29T15:56:31Z","timestamp":1209484591000},"page":"127-137","source":"Crossref","is-referenced-by-count":68,"title":["Brachy\u2013syndactyly caused by loss of <i>Sfrp2<\/i> function"],"prefix":"10.1002","volume":"217","author":[{"given":"Roy","family":"Morello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry K.","family":"Bertin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Schlaubitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad 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