Choroideremia gene product affects trophoblast development and vascularization in mouse extra-embryonic tissues

• Published in: Developmental biology 2004-08, Vol.272 (1), p.53-65
• Main Authors: Shi, Wei, van den Hurk, José A.J.M, Alamo-Bethencourt, Victor, Mayer, Wolfgang, Winkens, Huub J, Ropers, Hans-Hilger, Cremers, Frans P.M, Fundele, Reinald
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - genetics; Alkyl and Aryl Transferases - metabolism; Animals; Backcross analysis; Blood Vessels - embryology; Blood Vessels - physiology; Breeding; Choroideremia; Embryo, Mammalian - blood supply; Eye - pathology; Female; Fetal Death - genetics; Gene Expression Regulation, Developmental; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Placenta; Placenta - pathology; Polyploidy; Pregnancy; Tetraploid (4n) aggregation; Trophoblast; Trophoblasts - physiology; X Chromosome; Y Chromosome; Yolk sac; Yolk Sac - blood supply; Yolk Sac - pathology
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2004.04.016

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.