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

Irina V. Grigorieva, Samantha Mirczuk, Katherine U. Gaynor, M. Andrew Nesbit, Elena F. Grigorieva, Qiaozhi Wei, Asif Ali, Rebecca J. Fairclough, Joanna M. Stacey, Michael J. Stechman, Radu Mihai, Dorota Kurek, William D. Fraser, Tertius Hough, Brian G. Condie, Nancy Manley, Frank Grosveld, Rajesh V. Thakker

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2144-2155
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number6
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

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Neuroglia
Transcription Factors
Thymus Gland
Embryonic Structures
Calcium
Hypoparathyroidism
Parathyroid Glands
Chromatin Immunoprecipitation
Zinc Fingers
Deafness
Luciferases
Parathyroid Hormone
Vitamin D
Stem Cells
Diet
Kidney
Mutation
Mortality
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2. / Grigorieva, Irina V.; Mirczuk, Samantha; Gaynor, Katherine U.; Nesbit, M. Andrew; Grigorieva, Elena F.; Wei, Qiaozhi; Ali, Asif; Fairclough, Rebecca J.; Stacey, Joanna M.; Stechman, Michael J.; Mihai, Radu; Kurek, Dorota; Fraser, William D.; Hough, Tertius; Condie, Brian G.; Manley, Nancy; Grosveld, Frank; Thakker, Rajesh V.

In: Journal of Clinical Investigation, Vol. 120, No. 6, 01.06.2010, p. 2144-2155.

Research output: Contribution to journalArticle

Grigorieva, IV, Mirczuk, S, Gaynor, KU, Nesbit, MA, Grigorieva, EF, Wei, Q, Ali, A, Fairclough, RJ, Stacey, JM, Stechman, MJ, Mihai, R, Kurek, D, Fraser, WD, Hough, T, Condie, BG, Manley, N, Grosveld, F & Thakker, RV 2010, 'Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2', Journal of Clinical Investigation, vol. 120, no. 6, pp. 2144-2155. https://doi.org/10.1172/JCI42021
Grigorieva, Irina V. ; Mirczuk, Samantha ; Gaynor, Katherine U. ; Nesbit, M. Andrew ; Grigorieva, Elena F. ; Wei, Qiaozhi ; Ali, Asif ; Fairclough, Rebecca J. ; Stacey, Joanna M. ; Stechman, Michael J. ; Mihai, Radu ; Kurek, Dorota ; Fraser, William D. ; Hough, Tertius ; Condie, Brian G. ; Manley, Nancy ; Grosveld, Frank ; Thakker, Rajesh V. / Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 6. pp. 2144-2155.
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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.",
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T1 - Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

AU - Grigorieva, Irina V.

AU - Mirczuk, Samantha

AU - Gaynor, Katherine U.

AU - Nesbit, M. Andrew

AU - Grigorieva, Elena F.

AU - Wei, Qiaozhi

AU - Ali, Asif

AU - Fairclough, Rebecca J.

AU - Stacey, Joanna M.

AU - Stechman, Michael J.

AU - Mihai, Radu

AU - Kurek, Dorota

AU - Fraser, William D.

AU - Hough, Tertius

AU - Condie, Brian G.

AU - Manley, Nancy

AU - Grosveld, Frank

AU - Thakker, Rajesh V.

PY - 2010/6/1

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N2 - 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.

AB - 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.

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