title: Basement membrane fragility underlies embryonic lethality in fukutin-null mice.
abstract: Fukuyama-type congenital muscular dystrophy (FCMD), associated with brain malformation due to defects in neuronal migration, is caused by mutations in fukutin. Several lines of evidence suggest that the fukutin protein plays a pivotal role in synthesis of O-mannosyl sugar moieties of alpha-dystroglycan, a cell surface laminin receptor. Here, through targeted disruption of the orthologous mouse fukutin gene, we show that the fukutin protein is essential, as homozygous-null embryos die by E9.5 of gestation. Fukutin-null embryos show phenotypic diversity, features of which include growth retardation, folding of the egg cylinder, leakage of maternal red blood cells into the yolk sac cavity, and an increased number of apoptotic cells in the ectoderm. Loss of immunoreactivity against sugar moieties in alpha-dystroglycan suggests a reduced laminin-binding capacity. Ultrastructural analysis shows thin and breached basement membranes (BMs). BM fragility may underlie all of these abnormal phenotypes, and maintenance of BM function may require fukutin-mediated glycosylation of alpha-dystroglycan early in embryonic development.
authors.affiliation: Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurahashi
authors.forename: Mariko
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Chikara
authors.initials: C
authors.lastname: Meno
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeda
authors.forename: Masato
authors.initials: M
authors.lastname: Horie
authors.forename: Hiroki
authors.initials: H
authors.lastname: Otani
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D049030:Dystroglycans / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D006031:Glycosylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D014166:Transferases
chemical_list: D011506:Proteins; D049030:Dystroglycans; C491879:Fcmd protein, mouse; D014166:Transferases