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Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.
Qu S, Niswender KD, Ji Q, van der Meer R, Keeney D, Magnuson MA, Wisdom R
(1997) Development 124: 3999-4008
MeSH Terms: Amino Acid Sequence, Animals, Extremities, Eye Proteins, Gene Expression Regulation, Developmental, Homeodomain Proteins, Mice, Mice, Mutant Strains, Molecular Sequence Data, Polydactyly, Sequence Alignment, Zebrafish Proteins
Show Abstract · Added February 23, 2011
Correct development of the limb is dependent on coordination between three distinct signaling centers. Recently, fibroblast growth factor-4 has been identified as a crucial determinant of AER function, which directs limb bud outgrowth, and Sonic hedgehog has been identified as a signaling molecule that mediates ZPA function, which specifies anterior-posterior patterning in the developing limb bud. In addition, Shh and FGF-4 reciprocally reinforce each other's expression via a positive feedback loop, providing a molecular basis for the coordination of limb bud outgrowth and anterior-posterior patterning. The mechanisms by which these signaling centers come to occupy their normal positions in the posterior limb bud during development are not understood. Here we identify and characterize Alx-4, a gene that encodes a paired-type homeodomain protein. Alx-4 is expressed in several populations of mesenchymal cells, including mesenchymal cells in the anterior limb bud, and mice homozygous for targeted disruption of the Alx-4 gene have multiple abnormalities, including preaxial polydactyly. The polydactyly is associated with the formation of an ectopic anterior ZPA, as indicated by anterior expression of Sonic hedgehog, HoxD13 and fibroblast growth factor-4. The expression of other candidate regulators of anterior-posterior positional information in the limb bud, including HoxB8 and Gli3, is not altered in Alx-4 mutant embryos. By chromosomal mapping experiments, Alx-4 is tightly linked to Strong's luxoid, a polydactylous mouse mutant. The results identify Alx-4 as a determinant of anterior-posterior positional identity in the limb and a component of a regulatory program that restricts ZPA formation to the posterior limb bud mesenchyme.
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12 MeSH Terms
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
(1997) Dev Biol 188: 235-47
MeSH Terms: Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Bone and Bones, 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
Show Abstract · Added January 20, 2012
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.
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31 MeSH Terms