TY - JOUR
T1 - Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4
AU - Dunn, N. Ray
AU - Winnier, Glenn E.
AU - Hargett, Linda K.
AU - Schrick, Jeffrey J.
AU - Fogo, Agnes B.
AU - Hogan, Brigid L.M.
N1 - Funding Information:
We thank Drs. C.-c. Hui, Christopher Wright, and Lee Niswander for generous advice and encouragement and Lucy Liaw for establishing the 1A10H line. We also thank Drs. David Threadgill, David Greenstein, and Lilliana Solnica-Krezel and laboratory colleagues for many valuable discussions and comments on the manuscript, Julie Blackwell and Lorene Batts for skilled technical assistance, and Dr. Shimian Qu for graciously providing Figure 4C. This work was supported by NIH HD28955. N.R.D. acknowledges support from the multidisciplinary Viruses, Nucleic Acids, and Cancer NIH Predoctoral Training Grant 5T32CA09385. B.L.M.H. is an Investigator of the Howard Hughes Medical Institute.
PY - 1997/8/15
Y1 - 1997/8/15
N2 - 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 A1x4(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); A1x4(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.
AB - 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 A1x4(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); A1x4(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.
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U2 - 10.1006/dbio.1997.8664
DO - 10.1006/dbio.1997.8664
M3 - Article
C2 - 9268572
AN - SCOPUS:0031571651
SN - 0012-1606
VL - 188
SP - 235
EP - 247
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -