Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2.
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.
Grigorieva
Irina V
IV
Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, United Kingdom.
Mirczuk
Samantha
S
Gaynor
Katherine U
KU
Nesbit
M Andrew
MA
Grigorieva
Elena F
EF
Wei
Qiaozhi
Q
Ali
Asif
A
Fairclough
Rebecca J
RJ
Stacey
Joanna M
JM
Stechman
Michael J
MJ
Mihai
Radu
R
Kurek
Dorota
D
Fraser
William D
WD
Hough
Tertius
T
Condie
Brian G
BG
Manley
Nancy
N
Grosveld
Frank
F
Thakker
Rajesh V
RV
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005796:Genes; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D007011:Hypoparathyroidism / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010280:Parathyroid Glands / Q000166:cytology* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics
C523486:Gcm2 protein, mouse; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta