Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
Irina V. Grigorieva, … , Frank Grosveld, Rajesh V. Thakker
Irina V. Grigorieva, … , Frank Grosveld, Rajesh V. Thakker
Published May 17, 2010
Citation Information: J Clin Invest. 2010;120(6):2144-2155. https://doi.org/10.1172/JCI42021.
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Research Article Endocrinology

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

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.

Authors

Irina V. Grigorieva, Samantha Mirczuk, Katherine U. Gaynor, M. Andrew Nesbit, Elena F. Grigorieva, Qiaozhi Wei, Asif Ali, Rebecca J. Fairclough, Joanna M. Stacey, Michael J. Stechman, Radu Mihai, Dorota Kurek, William D. Fraser, Tertius Hough, Brian G. Condie, Nancy Manley, Frank Grosveld, Rajesh V. Thakker

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Figure 1

Effects of low calcium/vitamin D diet on survival and plasma calcium and PTH concentrations.

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Effects of low calcium/vitamin D diet on survival and plasma calcium and...
(A) Gata3+/+ (wild-type) and Gata3+/– mice were placed at weaning (day 0) on a low calcium (0.001%)/vitamin D (0.0 iU/g) diet. Survival of Gata3+/– mice on the low calcium/vitamin D diet was significantly reduced. Sudden death occurred in Gata3+/– mice after 13 days on the low calcium/vitamin D diet. By day 27, there were less than 50% Gata3+/– mice surviving, and the study was terminated. In contrast, more than 95% of the Gata3+/+ mice survived (P < 0.001). Numbers of mice in each group are indicated on the right, and number of deaths are shown in parentheses. (B) Plasma-adjusted calcium and PTH concentrations were assessed 12 days after weaning while on control (0.95% calcium and 4.5 iU/g vitamin D) or low calcium/vitamin D diets. Gata3+/+ and Gata3+/– mice had similar plasma calcium concentrations on the control diet but became significantly hypocalcemic on the low calcium/vitamin D diet, although the Gata3+/– mice had significantly lower plasma calcium concentrations than their Gata3+/+ littermates. (C) Gata3+/+ and Gata3+/– mice had similar plasma PTH concentrations on the control diet, and this rose significantly in response to the low calcium/vitamin D diet, although the elevation in plasma PTH was less in the Gata3+/– mice. Gata3+/+ (black bars); Gata3+/– (gray bars). Error bars represent SEM. #P < 0.000001, Gata3+/+ mice on control versus low diet; ϕP < 0.000001, Gata3+/– mice on control versus low diet; *P < 0.01.