HAPLOINSUFFICIENT PHENOTYPES IN BMP4 HETEROZYGOUS NULL MICE AND MODIFICATION BY MUTATIONS IN GLI3 AND ALX4

Bone morphogenetic protein 4 (Bmp4), a vertebrate homolog of Drosophil a decapentaplegic (dpp), encodes a signaling protein with multiple fun ctions during embryogenesis. Most mouse embryos homozygous for the Bmp 4(tm1blh) null allele die around the time of gastrulation, with little or no mesoderm. Two independently derived Bmp4(tm1) mutations were ba ckcrossed onto the C57BL/6 genetic background. Several independently e xpressed, incompletely penetrant abnormalities were observed in hetero zygotes, including cystic kidney, craniofacial malformations, micropht halmia, and preaxial polydactyly of the right hindlimb. In addition, h eterozygotes were consistently underrepresented at weaning. These resu lts indicate that Bmp4 gene dosage is essential for the normal develop ment of a variety of organs and for neonatal viability. Two mutations that enhance the penetrance and expressivity of the polydactylous phen otype were identified: Gli3(XtJ) a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interrupt us, and Alx4(mt1rwm), a targeted mil mutation in a gene encoding a pai red class homeoprotein related to Drosophila aristaless. All double Bm p4(tm1); Gli3(XtJ) heterozygotes have extensive anterior di,ait abnorm alities of both fore-and hindlimbs, while all double Bmp4(tm1); Alx4(t m1) heterozygotes display ectopic anterior digits only on the hindlimb s. These genetic interactions suggest a model for the multigenic contr ol of anterior digit patterning during vertebrate limb development. (C ) 1997 Academic Press.