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DYRK1A BAC transgenic mouse: a new model of thyroid dysgenesis in Down syndrome
Dulanjalee Kariyawasam1, Latif Rachdi, Aurore Carré
1Inserm 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.
Insights
Transgenic Dyrk1A mice exhibit thyroid developmental and functional impairments, mirroring thyroid dysgenesis observed in Down syndrome (DS). This mouse model effectively simulates DS-related thyroid abnormalities for further research.
Area of Science:
- Endocrinology
- Developmental Biology
- Genetics
Background:
- Down syndrome (DS) is frequently associated with thyroid abnormalities, including hypothyroidism and thyroid hypoplasia, potentially worsening cognitive deficits.
- The Dyrk1A gene is implicated in DS pathogenesis, and its overexpression may influence developmental processes.
Purpose of the Study:
- To evaluate the Dyrk1A(+/++) transgenic mouse as a model for studying thyroid dysgenesis in Down syndrome.
- To investigate the impact of Dyrk1A gene triplication on embryonic and adult thyroid development and function.
Main Methods:
- Analyzed embryonic thyroid development (E13.5-E17.5) in wild-type (WT) and Dyrk1A(+/++) mice using immunofluorescence for key thyroid markers (Nkx2-1, thyroglobulin, T4).
- Quantified expression of thyroidogenesis transcription factors (Nkx2-1, Pax8, Foxe1) via RT-PCR.
- Assessed adult phenotype (8-12 weeks) by measuring plasma T4 and TSH levels, thyroid weight, and performing histological analysis.
Main Results:
- Dyrk1A(+/++) embryonic thyroids showed significantly increased size at E15.5 but reduced differentiated follicular surface area by E17.5.
- Elevated RNA levels of Nkx2-1, Foxe1, and Pax8 were observed in Dyrk1A(+/++) embryonic thyroids.
- Adult Dyrk1A(+/++) mice displayed lower plasma T4, heavier thyroids, and disorganized thyroid histology compared to WT controls.
Conclusions:
- Overexpression of Dyrk1A directly impairs thyroid embryogenesis, function, and morphology.
- The observed adult thyroid phenotype in Dyrk1A(+/++) mice is likely a consequence of developmental abnormalities.
- The Dyrk1A(+/++) mouse serves as a suitable model for investigating thyroid dysgenesis associated with 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.
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