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One possible explanation for these observations is that although both of these FGF family members contribute to limb development, Fgf8 has functions that Fgf4 cannot perform. To test this hypothesis, we used a novel method to substitute Fgf4 for Fgf8 expression in the developing limb bud by concomitantly activating a conditional Fgf4 gain-of-function allele and inactivating an Fgf8 loss-of-function allele in the same cells via Cre-mediated recombination. Our data show that when Fgf4 is expressed in place of Fgf8, all of the skeletal defects caused by inactivation of Fgf8 are rescued, conclusively demonstrating that FGF4 can functionally replace FGF8 in limb skeletal development. We also show that the increase in FGF signaling that occurs when the Fgf4gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit (postaxial polydactyly), as well as cutaneous syndactyly between all the digits. These data underscore the importance of controlling the level of FGF gene expression for normal limb development.<\/jats:p>","DOI":"10.1242\/dev.02172","type":"journal-article","created":{"date-parts":[[2005,11,25]],"date-time":"2005-11-25T01:13:33Z","timestamp":1132881213000},"page":"33-42","source":"Crossref","is-referenced-by-count":82,"title":["Increasing<i>Fgf4<\/i>expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of<i>Fgf8<\/i>function"],"prefix":"10.1242","volume":"133","author":[{"given":"Pengfei","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Anatomy and Program in Developmental Biology, School of Medicine\u0300 University of California at San Francisco San Francisco, CA 94143-2711, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Minowada","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Program in Developmental Biology, School of Medicine\u0300 University of California at San Francisco San Francisco, CA 94143-2711, USA."},{"name":"Department of Medicine, Division of Pulmonary and Critical Care Medicine, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland, Cleveland, OH 44106, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Program in Developmental Biology, School of Medicine\u0300 University of California at San Francisco San Francisco, CA 94143-2711, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2021042605292362900_REF1","doi-asserted-by":"crossref","unstructured":"Adamska, M., MacDonald, B. 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