title: 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.affiliation: 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.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Grigorieva
authors.forename: Samantha
authors.initials: S
authors.lastname: Mirczuk
authors.forename: Katherine U
authors.initials: KU
authors.lastname: Gaynor
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Nesbit
authors.forename: Elena F
authors.initials: EF
authors.lastname: Grigorieva
authors.forename: Qiaozhi
authors.initials: Q
authors.lastname: Wei
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Fairclough
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Stacey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stechman
authors.forename: Radu
authors.initials: R
authors.lastname: Mihai
authors.forename: Dorota
authors.initials: D
authors.lastname: Kurek
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: Tertius
authors.initials: T
authors.lastname: Hough
authors.forename: Brian G
authors.initials: BG
authors.lastname: Condie
authors.forename: Nancy
authors.initials: N
authors.lastname: Manley
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: 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
chemical_list: C523486:Gcm2 protein, mouse; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta