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Mechanistic insight into X-linked Hypopituitarism: the role of SOX3

Abstract : OX3, a transcription factor, is expressed in the embryonic central nervous system (CNS) including the hypothalamic primordium. Sox3 knockout mice have pituitary hormone deficiencies as well as CNS abnormalities. SOX3 duplications in humans cause a condition known as X-linked Hypopituitarism (XH). XH patients have reduced growth hormone levels, variable deficiencies of other pituitary hormone, and on occasion, mental retardation. We modeled this form of XH, and found that Sox3 transgenic mice have CNS abnormalities ranging from reduced telencephalic vesicles to hippocampus dysgenesis. Other defects include a reduction in GHRH neurons, dwarfism, abnormal gait and enlarged ventricles in the brain. All Sox3 transgenic mice display normal pituitary morphology as well as hormone secreting lineages. An additional mechanism causing XH are mutations in SOX3 that increase the 15 amino acid polyalanine tract by 7 or 11 extra alanines (SOX3 22Ala and SOX3 26Ala). Both mutant proteins form cytoplasmic aggregates, nuclear inclusions, and perinuclear aggregates in cell lines and chick neuroepithelium. Immunohistochemical staining show that perinuclear aggregates are located at the Microtubule Organising Center, and are ensheathed in vimentin, and therefore appear to be aggresomes. We also show that Gal4-SOX3 fusions are transcriptionally active, and that both SOX3 22Ala and SOX3 26Ala have markedly reduced transcriptional activity. Our results suggest that increased dosage of SOX3 due to duplications in the X chromosome, or decreased dosage of SOX3 due to aggregate formation of the mutant forms of SOX3, both lead to CNS abnormalities via effects on neurogenesis.
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Déposant : Migration Prodinra <>
Soumis le : jeudi 4 juin 2020 - 05:12:15
Dernière modification le : mardi 22 septembre 2020 - 11:24:03




J. T. Wong, N. Solomon, K. Rizzoti, R. Lovell-Badge, P. G. Farlie, et al.. Mechanistic insight into X-linked Hypopituitarism: the role of SOX3. 15. International Society of Developmental Biologists Congress 2005, Sep 2005, Sydney, France. ELSEVIER SCIENCE BV, Mechanisms of Development, 122 (Supplement 1), 2005, FROM EGG TO ADULT: CONSTRUCTING THE COMPLEXITY OF LIFE. ⟨10.1016/j.mod.2005.06.010⟩. ⟨hal-02760609⟩



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