PATHOGENESIS OF ECTRODACTYLY IN THE DACTYLAPLASIA MOUSE - ABERRANT CELL-DEATH OF THE APICAL ECTODERMAL RIDGE

Dactylaplasia, or Dac, was recently mapped to the distal portion of mo use chromosome 19 and shown to be inherited as an autosomal semi-domin ant trait characterized by missing central digital rays. The most comm on? locus for human split hand split foot malformation, also typically characterized by missing central digital rays, is 10q25, a region of synteny to the Dac locus. The Dac mouse appears to be an ideal genotyp ic and phenotypic model for this human malformation syndrome. Several genes lie in this region of synteny, however, only Fibroblast Growth F actor 8, or Fgf-8, has been implicated to have a role in limb developm ent. We demonstrate that the developmental mechanism underlying loss o f central rays in Dac limbs is dramatic cell death of the apical ectod ermal ridge, or AER. This cell death pattern is apparent in E10.5-11.5 Dac limb buds stained with the supravital dye Nile Blue Sulfate. We d emonstrate that Fgf8 expression in wild type limbs colocalizes spatial ly and temporally with AER cell death in Dac limbs. Furthermore, in ou r mapping panel, there is an absence of recombinants between Fgf-8 and the Dac locus in 133 backcross progeny with a median linkage estimate of approximately 0.5 cM. Thus, our results demonstrate that cell deat h of the AER in Dac limbs silences the role of the AER as key regulato r of limb outgrowth, and that Fgf-8 is a strong candidate for the caus e of the Dac phenotype. (C) 1997 Wiley-Liss, Inc.