Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4.

Dunn NR, Winnier GE, Hargett LK, Schrick JJ, Fogo AB, Hogan BL
Dev Biol. 1997 188 (2): 235-47

PMID: 9268572 · DOI:10.1006/dbio.1997.8664

Bone morphogenetic protein 4 (Bmp4), a vertebrate homolog of Drosophila decapentaplegic (dpp), encodes a signaling protein with multiple functions during embryogenesis. Most mouse embryos homozygous for the Bmp4(tm1blh) null allele die around the time of gastrulation, with little or no mesoderm. Two independently derived Bmp4(tm1) mutations were backcrossed onto the C57BL/6 genetic background. Several independently expressed, incompletely penetrant abnormalities were observed in heterozygotes, including cystic kidney, craniofacial malformations, microphthalmia, and preaxial polydactyly of the right hindlimb. In addition, heterozygotes were consistently underrepresented at weaning. These results indicate that Bmp4 gene dosage is essential for the normal development of a variety of organs and for neonatal viability. Two mutations that enhance the penetrance and expressivity of the polydactylous phenotype were identified: Gli3(XtJ), a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interruptus, and Alx4(tm1rwm), a targeted null mutation in a gene encoding a paired class homeoprotein related to Drosophila aristaless. All double Bmp4(tm1); Gli3(XtJ) heterozygotes have extensive anterior digit abnormalities of both fore- and hindlimbs, while all double Bmp4(tm1); Alx4(tm1) heterozygotes display ectopic anterior digits only on the hindlimbs. These genetic interactions suggest a model for the multigenic control of anterior digit patterning during vertebrate limb development.

MeSH Terms (31)

Animals Bone and Bones Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins Congenital Abnormalities Crosses, Genetic DNA-Binding Proteins Embryonic and Fetal Development Female Fetal Death Gastrula Genotype Heterozygote Kidney Kruppel-Like Transcription Factors Male Mesoderm Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Mutagenesis Nerve Tissue Proteins Osteogenesis Phenotype Polydactyly Repressor Proteins Sex Characteristics Transcription Factors Xenopus Proteins Zinc Finger Protein Gli3

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