title: Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4.
abstract: 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.
authors.affiliation: Department of Cell Biology, Vanderbilt University Medical School, Nashville, Tennessee, 37232-2175, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Dunn
authors.forename: G E
authors.initials: GE
authors.lastname: Winnier
authors.forename: L K
authors.initials: LK
authors.lastname: Hargett
authors.forename: J J
authors.initials: JJ
authors.lastname: Schrick
authors.forename: A B
authors.initials: AB
authors.lastname: Fogo
authors.forename: B L
authors.initials: BL
authors.lastname: Hogan
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000172:deficiency* / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology; D000013:Congenital Abnormalities / Q000235:genetics*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D005260:Female; D005313:Fetal Death; D005775:Gastrula; D005838:Genotype; D006579:Heterozygote; D007668:Kidney / Q000196:embryology / Q000473:pathology; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016296:Mutagenesis; D009419:Nerve Tissue Proteins; D010012:Osteogenesis; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics; D012097:Repressor Proteins; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; C525812:bmp4 protein, Xenopus