title: Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice.
abstract: Hypodactyly (Hoxa13Hd) mice have a small deletion within the coding sequence of Hoxa13 and a limb phenotype that is more severe than that of mice with an engineered null allele of Hoxa13. We used whole-mount in situ hybridization, Nile blue sulfate staining and genetic crosses to determine the basis for the phenotypic differences between these two mutants. Expression of Hoxd13 was unaffected in Hoxa13-/- mice, but its domain was reduced at the anterior and posterior margins of the autopod in Hoxa13Hd/Hd limb buds. The maturation of Hoxd11 expression was delayed and expression of Hoxa11 failed to become restricted to the autopod/zeugopod junction in both Hoxa13Hd/Hd and Hoxa13-/- limb buds compared to wild-type mice. Fgf8 expression was normal in both Hoxa13Hd/Hd and Hoxa13-/- mice throughout limb development. A dramatic increase in cell death was observed in limb bud mesenchyme of Hoxa13Hd/Hd mice as early as E11.5 but not in mice homozygous for the null allele. Genetic background was excluded as the basisforthe phenotypic differences. Compound heterozygotes (Hoxa13-/Hd) displayed an intermediate phenotype relative to both homozygotes suggesting that Hoxa13Hd has an effect on the development of the autopod beyond that which may result from a loss of HOXA13 protein. These results showthat Hoxa13Hd has a negative effect on the survival of the mesenchyme in the autopod, unlike the Hoxa13 null mutation, that cannot be explained by a failure of the AER to express Fgfs. In addition, at least one target of HOXA13 may be Hoxa11.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor 48109-0618, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Post
authors.forename: J W
authors.initials: JW
authors.lastname: Innis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005121:Extremities / Q000196:embryology; D005260:Female; D015870:Gene Expression; D005801:Genes, Homeobox; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C099959:homeobox protein HOXA13