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

IV Grigorieva, S Mirczuk, KU Gaynor, MA Nesbit, EF Grigorieva, QZ Wei, A Ali, RJ Fairclough, JM Stacey, MJ Stechman, R Mihai, Dorota Kurek, WD Fraser, T Hough, BG Condie, N Manley, Frank Grosveld, RV Thakker

Research output: Contribution to journalArticleAcademicpeer-review

91 Citations (Scopus)

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 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.
Original languageUndefined/Unknown
Pages (from-to)2144-2155
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number6
DOIs
Publication statusPublished - 2010

Cite this