title: Choroideremia gene product affects trophoblast development and vascularization in mouse extra-embryonic tissues.
abstract: Choroideremia (CHM) is a hereditary eye disease caused by mutations in the X-linked CHM gene. Disruption of the Chm gene in mice resulted in prenatal death of Chm-/Y males and Chm-/Chm+ females that had inherited the mutation from their mothers. Male chimeras and Chm+/Chm- females with paternal transmission of the mutation were viable and had photoreceptor degeneration reminiscent of human choroideremia. Here, we show that Chm-/Y males and Chm-/Chm+ females were retarded at e7.5 and died before e11.5 due to multiple defects of the extra-embryonic tissues. Mutant embryos exhibited deficiency of diploid trophoblasts associated with overabundance of giant cells. In yolk sac and placenta, severe defects in vasculogenesis were obvious. Chm-/Y males exhibited more pronounced phenotypes than Chm-/Chm+ females. The lethal genotypes could be rescued by tetraploid aggregation. Chm-/Chm+ females, but not Chm-/Y males, could also be rescued when their Chm+/Chm- mothers were mated with Mus spretus males. Backcross analysis suggested that the viability of interspecies hybrid Chm-/Chm+ females may be due to expression from the Chm allele on the M. spretus X-chromosome rather than a modifier effect. Our results demonstrate that Chm is essential for diploid trophoblast development and plays a role in the vascularization in placenta and yolk sac.
authors.affiliation: Max-Planck-Institute for Molecular Genetics, Berlin-Dahlem, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: José A J M
authors.initials: JA
authors.lastname: van den Hurk
authors.forename: Victor
authors.initials: V
authors.lastname: Alamo-Bethencourt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mayer
authors.forename: Huub J
authors.initials: HJ
authors.lastname: Winkens
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Reinald
authors.initials: R
authors.lastname: Fundele
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000196:embryology* / Q000502:physiology; D001947:Breeding; D004622:Embryo, Mammalian / Q000098:blood supply*; D005123:Eye / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010920:Placenta / Q000473:pathology; D011123:Polyploidy; D011247:Pregnancy; D014327:Trophoblasts / Q000502:physiology*; D014960:X Chromosome; D014998:Y Chromosome; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology
chemical_list: D019883:Alkyl and Aryl Transferases