Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 6, Pages 2144-2155Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI42021
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Funding
- Medical Research Council (MRC), UK [69825289 [2004]]
- European Molecular Biology Organization (EMBO)
- MRC [G9825289, MC_UP_1502/1] Funding Source: UKRI
- Medical Research Council [G9825289, MC_UP_1502/1] Funding Source: researchfish
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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 EMS, 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.
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