title: DYRK1A BAC transgenic mouse: a new model of thyroid dysgenesis in Down syndrome.
abstract: The most common thyroid abnormality among Down syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onward, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by bacterial artificial chromosome engineering (mBACTgDyrk1A), have 3 copies of the Dyrk1A gene. The objective is to determine whether this transgenic Dyrk1A (Dyrk1A(+/++)) mouse is an adequate murine model for the study of thyroid dysgenesis in DS. Embryonic thyroid development from embryonic day 13.5 (E13.5) to E17.5 was analyzed in wild-type (WT) and Dyrk1A(+/++) mice by immunofluorescence with anti-Nkx2-1, anti-thyroglobulin, and anti-T4 antibodies, markers of early thyroid development, hormonogenesis, and final differentiation, respectively. The expression of transcription factors Nkx2-1, Pax8, and Foxe1 involved in thyroidogenesis were studied by quantitative RT-PCR at the same embryonic stages. We then compared the adult phenotype at 8 to 12 weeks in Dyrk1A(+/++) and WT mice for T4 and TSH levels, thyroidal weight, and histological analysis. Regarding thyroidal development, at E15.5, Dyrk1A(+/++) thyroid lobes are double the size of WT thyroids (P = .01), but the thyroglobulin stained surface in Dyrk1A(+/++) thyroids is less than a third as large at E17.5 (P = .04) and their differentiated follicular surface half the size (P = .004). We also observed a significant increase in Nkx2-1, Foxe1, and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A(+/++) embryonic thyroids. Dyrk1A(+/++) young adult mice have significantly lower plasma T4 (2.4 ng/mL versus WT, 3.7 ng/mL; P = 0.019) and nonsignificantly higher plasma TSH (114 mUI/L versus WT, 73mUI/L; P = .09). In addition, their thyroids are significantly heavier (P = .04) and exhibit large disorganized regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid phenotype is probably a result of embryogenetic impairment. The Dyrk1A(+/++) mouse can be considered a suitable study model for thyroid dysgenesis in DS.
authors.affiliation: Inserm U1016 (D.K., L.R., A.C., M.H., R.S., M.P.), 75014 Paris France; Imagine Institute (D.K., A.C., M.P.), Paris, France; Pediatric Endocrinology, Gynaecology and Diabetology Unit (D.K., M.P.), Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Diabetes and Obesity Research Laboratory (M.M.), Institut d'Investigacions Biomèdiques August Pi I Sunyer, 08036 Barcelona, Spain; Unité de Biologie Fonctionnelle et Adaptative (N.J., J.-M.D.), Centre National de Recherche Scientifique 4413, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; and Université Paris Descartes-Sorbonne Paris Cité (M.P.), 75006 Paris, France.
authors.forename: Dulanjalee
authors.initials: D
authors.lastname: Kariyawasam
authors.forename: Latif
authors.initials: L
authors.lastname: Rachdi
authors.forename: Aurore
authors.initials: A
authors.lastname: Carré
authors.forename: Mercè
authors.initials: M
authors.lastname: Martin
authors.forename: Marine
authors.initials: M
authors.lastname: Houlier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Delabar
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
mesh_terms: D000818:Animals; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050033:Thyroid Dysgenesis / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000196:embryology*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases