title: The effect of maternal diabetes on the Wnt-PCP pathway during embryogenesis as reflected in the developing mouse eye.
abstract: Embryopathies that develop as a consequence of maternal diabetes have been studied intensely in both experimental and clinical scenarios. Accordingly, hyperglycaemia has been shown to downregulate the expression of elements in the non-canonical Wnt-PCP pathway, such as the Dishevelled-associated activator of morphogenesis 1 (Daam1) and Vangl2. Daam1 is a formin that is essential for actin polymerization and for cytoskeletal reorganization, and it is expressed strongly in certain organs during mouse development, including the eye, neural tube and heart. Daam1(gt/gt) and Daam1(gt/+) embryos develop ocular defects (anophthalmia or microphthalmia) that are similar to those detected as a result of hyperglycaemia. Indeed, studying the effects of maternal diabetes on the Wnt-PCP pathway demonstrated that there was strong association with the Daam1 genotype, whereby the embryopathy observed in Daam1(gt/+) mutant embryos of diabetic dams was more severe. There was evidence that embryonic exposure to glucose in vitro diminishes the expression of genes in the Wnt-PCP pathway, leading to altered cytoskeletal organization, cell shape and cell polarity in the optic vesicle. Hence, the Wnt-PCP pathway appears to influence cell morphology and cell polarity, events that drive the cellular movements required for optic vesicle formation and that, in turn, are required to maintain the fate determination. Here, we demonstrate that the Wnt-PCP pathway is involved in the early stages of mouse eye development and that it is altered by diabetes, provoking the ocular phenotype observed in the affected embryos.
authors.affiliation: Grupo de Neurodesarrollo, Unidad de Gestión de Pediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Centro Superior de Investigaciones Científicas, Universidad de Sevilla, 41013 Seville, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: López-Escobar
authors.affiliation: Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, 41013 Sevilla, Spain.
authors.forename: David A
authors.initials: DA
authors.lastname: Cano
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), 41092 Sevilla, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Grupo de Neurodesarrollo, Unidad de Gestión de Pediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Centro Superior de Investigaciones Científicas, Universidad de Sevilla, 41013 Seville, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Felipe
authors.affiliation: Unidad de Experimentación animal. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Centro Superior de Investigaciones Científicas, Universidad de Sevilla, 41013 Seville, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Palma
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD) 41013 Sevilla, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Alcázar
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Henderson
authors.affiliation: Grupo de Neurodesarrollo, Unidad de Gestión de Pediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Centro Superior de Investigaciones Científicas, Universidad de Sevilla, 41013 Seville, Spain. pybot-ibis@us.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ybot-González
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D047108:Embryonic Development / Q000187:drug effects; D005123:Eye / Q000196:embryology* / Q000473:pathology; D005124:Eye Abnormalities / Q000196:embryology / Q000473:pathology; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011247:Pregnancy; D012097:Repressor Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C500365:Daam1 protein, mouse; D020741:rho GTP-Binding Proteins; D005947:Glucose
keywords: Daam1; Diabetes; Eye defects; Heart defects; Neural tube defects; Wnt-PCP pathway