Yingchun Wang1, Hiroki Shimizu1, Yun-Yan Xiang1,2, Junichi Sugihara1, Wei-Yang Lu2, Xiao-Hui Liao3, Hae-Ra Cho1,4, Hiroaki Toba1, Xiao-Hui Bai1, Sylvia L Asa5,6, Peter Arvan7, Samuel Refetoff3,8,9, Mingyao Liu1,4,10,11,12. 1. Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada. 2. Department of Physiology and Pharmacology, University of Western Ontario, London, Canada. 3. Department of Medicine and Chicago, Illinois, USA. 4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 5. Department of Pathology, University Health Network, Toronto, Ontario, Canada. 6. University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio, USA. 7. Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA. 8. Department of Pediatrics; and Chicago, Illinois, USA. 9. Department of Committee on Genetics; The University of Chicago, Chicago, Illinois, USA. 10. Department of Surgery, and University of Toronto, Toronto, Ontario, Canada. 11. Department of Medicine; and University of Toronto, Toronto, Ontario, Canada. 12. Department of Institute of Medical Science; Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract
Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored. Methods: Xb130-/- mice and their littermates were studied. Postnatal growth and growth hormone levels were measured, and responses to low or high-iodine diet, and levothyroxine treatment were examined. TH and thyrotropin in the serum and TH in the thyroid glands were quantified. Structure and function of thyrocytes in embryos and postnatal life were studied with histology, immunohistochemistry, immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction. Results: Xb130-/- mice exhibited transient growth retardation postnatally, due to congenital hypothyroidism with reduced TH synthesis and secretion, which could be rescued by exogenous thyroxine supplementation. The thyroid glands of Xb130-/- mice displayed diminished thyroglobulin iodination and release at both embryonic and early postnatal stages. XB130 was found mainly on the apical membrane of thyroid follicles. Thyroid glands of embryonic and postnatal Xb130-/- mice exhibited disorganized apical membrane structure, delayed folliculogenesis, and abnormal formation of thyroid follicle lumina. Conclusion: XB130 critically regulates folliculogenesis by maintaining apical membrane structure and function of thyrocytes, and its deficiency leads to congenital hypothyroidism.
Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored. Methods: Xb130-/- mice and their littermates were studied. Postnatal growth and growth hormone levels were measured, and responses to low or high-iodine diet, and levothyroxine treatment were examined. TH and thyrotropin in the serum and TH in the thyroid glands were quantified. Structure and function of thyrocytes in embryos and postnatal life were studied with histology, immunohistochemistry, immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction. Results: Xb130-/- mice exhibited transient growth retardation postnatally, due to congenital hypothyroidism with reduced TH synthesis and secretion, which could be rescued by exogenous thyroxine supplementation. The thyroid glands of Xb130-/- mice displayed diminished thyroglobulin iodination and release at both embryonic and early postnatal stages. XB130 was found mainly on the apical membrane of thyroid follicles. Thyroid glands of embryonic and postnatal Xb130-/- mice exhibited disorganized apical membrane structure, delayed folliculogenesis, and abnormal formation of thyroid follicle lumina. Conclusion: XB130 critically regulates folliculogenesis by maintaining apical membrane structure and function of thyrocytes, and its deficiency leads to congenital hypothyroidism.
Entities:
Keywords:
adaptor protein; cell polarity; congenital hypothyroidism; folliculogenesis; thyroglobulin release and iodination; thyroid hormone synthesis and secretion
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