Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb

Members of bone morphogenetic proteins (BMPs) play important roles in many aspects of vertebrate embryogenesis. In developing limbs, BMPs have been im plicated in control of anterior-posterior patterning, outgrowth, chondrogen esis, and apoptosis. These diverse roles of BMPs in limb development are ap parently mediated by different BMP receptors (BMPR). To identify the develo pmental processes in mouse limb possibly contributed by BMP receptor-IB (BM PR-IB), we generated transgenic mice misexpressing a constitutively active Bmpr-IB (caBmpr-IB). The transgene driven by the mouse Hoxb-6 promoter was ectopically expressed in the posterior mesenchyme of the forelimb bud, the lateral plate mesoderm, and the whole mesenchyme of the hindlimb bud. While the forelimbs appeared normal, the transgenic hindlimbs exhibited several phenotypes, including bifurcation, preaxial polydactyly, and posterior tran sformation of the anterior digit. However, the size of bones in the transge nic limbs seemed unaltered. Defects in stemum and ribs were also found. The bifurcation in the transgenic hindlimb occurred early in the limb developm ent (E10.5) and was associated with extensive cell death in the mesenchyme and occasionally in the apical ectodermal ridge (AER). Sonic hedgehog (Shh) and Patched (Pfc) expression appeared unaffected in the transgenic limb bu ds, suggesting that the BMPR-IB mediated signaling pathway is downstream fr om Shh. However, ectopic Fgf4 expression was found in the anterior AER, whi ch may account for the duplication of the anterior digit. An ectopic expres sion of Gremlin found in the transgenic limb bud would be responsible for t he ectopic Fgf4 expression The observations that Hoxd-12 and Hoxd-13 expres sion patterns were extended anteriorly provide a molecular basis for the po sterior transformation of the anterior digit. Together these results sugges t that BMPR-IB is the endogenous receptor to mediate the role of BMPs in an terior-posterior patterning and apoptosis in mouse developing limb. In addi tion, BMPR-IB may represent a critical component in the Shh/FGF4 feedback l oop by regulating Gremlin expression. (C) 2000 Academic Press.