title: Abnormal vascular development in zebrafish models for fukutin and FKRP deficiency.
abstract: Fukutin and fukutin-related protein (FKRP) are involved in the glycosylation of α-dystroglycan, a key receptor for basement membrane proteins. Aberrant α-dystroglycan glycosylation leads to a broad spectrum of disorders, ranging from limb girdle muscular dystrophy to Walker-Warburg syndrome. This is the first study investigating a role of fukutin and FKRP-mediated glycosylation in angiogenesis. Transgenic zebrafish expressing enhanced green fluorescent protein in blood vessels were treated with morpholino antisense oligonucleotides that blocked the expression of fukutin, FKRP and dystroglycan. All morphant fish showed muscle damage and vascular abnormalities at day 1 post-fertilization. Intersegmental vessels of somites failed to reach the dorsal longitudinal anastomosis and in more severe phenotypes retracted further or were in some cases even completely missing. In contrast, the eye vasculature was distorted in both fukutin and FKRP morphants, but not in dystroglycan morphants or control fish. The eye size was also smaller in the fukutin and FKRP morphants when compared with dystroglycan knockdown fish and controls. In general, the fukutin morphant fish had the most severe skeletal muscle and eye phenotype. Our findings suggest that fukutin and FKRP have functions that affect ocular development in zebrafish independently of dystroglycan. Despite anecdotal reports about vascular abnormalities in patients affected by dystroglycanopathies, the clinical relevance of such lesions remains unclear and should be subject to further review and investigations.
authors.affiliation: International Centre for Life, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Wood
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Jepson
authors.forename: Steve H
authors.initials: SH
authors.lastname: Laval
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000276:immunology; D001808:Blood Vessels / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology* / Q000473:pathology; D049030:Dystroglycans / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005123:Eye / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D016695:Glycosyltransferases / Q000172:deficiency* / Q000378:metabolism; D023421:Models, Animal; D060172:Morpholinos / Q000494:pharmacology; D010590:Phalloidine / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1; D019170:Somites / Q000002:abnormalities / Q000098:blood supply / Q000187:drug effects / Q000196:embryology; D013194:Staining and Labeling; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000906:Antibodies; D060172:Morpholinos; D051789:Proto-Oncogene Protein c-fli-1; D029961:Zebrafish Proteins; D049030:Dystroglycans; D010590:Phalloidine; C532743:FKRP protein, zebrafish; C560200:FKTN protein, zebrafish; D016695:Glycosyltransferases