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.

Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation

“…These effects were accompanied with the reduction of Gata3, suggesting that this Notch-target is a downstream mediator of Notch activity during common primordium development. In agreement, heterozygous mice mutants for Gata3 have smaller T/PT common primordium with fewer cells expressing Gcm2 (Grigorieva et al, 2010).…”

“…1A). Interestingly, Gata3 has been previously shown to be involved in parathyroid formation (Grigorieva et al, 2010).…”

Mouse models for inherited endocrine and metabolic disorders

“…Gata3 C/K mice had smaller parathyroid-thymus primordia at E11.5, with fewer cells expressing Gcm2, and Gata3 K/K mice had no primordia after E12.5, with a complete absence of Gcm2-expressing cells, indicating a defect of parathyroid gland development in both Gata3 C/K and Gata3 K/K mice (Grigorieva et al 2010). Indeed, GATA3 bound to a functional double GATA motif in the GCMB promoter in human parathyroid adenoma cells, demonstrating a direct link between GATA3 and GCMB as part of a critical transcriptional cascade in parathyroid development (Grigorieva et al 2010). Gata3 C/K mice had hearing loss starting in the early postnatal period, and progressing through adulthood (van der Wees et al 2004).…”

“…C/K mice were unable to mount the appropriate parathyroid response, and thus had a lower plasma PTH and calcium than their wild-type littermates, as well as smaller parathyroid glands with lower proliferation rates (Grigorieva et al 2010). Gata3 C/K mice had smaller parathyroid-thymus primordia at E11.5, with fewer cells expressing Gcm2, and Gata3 K/K mice had no primordia after E12.5, with a complete absence of Gcm2-expressing cells, indicating a defect of parathyroid gland development in both Gata3 C/K and Gata3 K/K mice (Grigorieva et al 2010).…”

“…5 due to apoptotic cell death. GCM2 and GATA3 form part of a transcriptional cascade that facilitates parathyroid development (Liu et al 2007, Grigorieva et al 2010.…”