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Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

Grigorieva, Irina V., Mirczuk, Samantha, Gaynor, Katherine U., Nesbit, M. Andrew, Grigorieva, Elena F., Wei, Qiaozhi, Ali, Asif, Fairclough, Rebecca J., Stacey, Joanna M., Stechman, Michael J., Mihai, Radu, Kurek, Dorota, Fraser, William D., Hough, Tertius, Condie, Brian G., Manley, Nancy, Grosveld, Frank and Thakker, Rajesh V. 2010. Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2. Journal of Clinical Investigation 120 (6) , pp. 2144-2155. 10.1172/JCI42021

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Abstract

Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/– mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/– mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/– mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/– embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3–/– embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of Acceptance: 31 March 2010
Last Modified: 15 Jan 2021 15:00
URI: https://orca.cardiff.ac.uk/id/eprint/137621

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