SFEBES2009 Oral Communications Bone and parathyroid (8 abstracts)
Mice deleted for the transcription factor Gata3 have fewer parathyroid cells expressing Gcm2, develop hypocalcaemia and have an earlier onset of mortality when challenged with a low calcium-vitamin D diet
Irina Grigorieva 1 , Samantha Mirczuk 1 , Katie Gaynor 1 , M Andrew Nesbit 1 , Elena Grigorieva 2 , Qiaozhi Wei 3 , Jacqueline van der Wees 4 , William Fraser 5 , Tertius Hough 6 , Nancy Manley 3 , Frank Grosveld 4 & Rajesh Thakker 1
1University of Oxford, Oxford, UK; 2The National Institute for Medical Research, London, UK; 3University of Georgia, Athens, Georgia, USA; 4Erasmus University, Rotterdam, The Netherlands; 5Royal Liverpool University Hospital, Liverpool, UK; 6Medical Research Council, Harwell, UK.
Heterozygous mutations of GATA3, a dual zinc-finger transcription factor, cause the hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome. To study the role of GATA3 in parathyroid function we have investigated Gata3+/− mice for hypoparathyroidism. Gata3+/− and Gata3+/+ mice were challenged at weaning with a diet low in calcium (0.001%) and vitamin D (0.0 IU/g). The low calcium-vitamin D diet led to a significantly higher mortality amongst the Gata3+/− mice compared to Gata3+/+ mice (56 vs 3%, P<0.001). Moreover, plasma concentrations of calcium and PTH, measured before the onset of mortality, were significantly lower in Gata3+/− mice compared to Gata3+/+ mice (2.01±0.23 vs 2.16±0.29 mmol/l calcium; 73.74±22.06 vs 86.44±22.97 pmol/l PTH; P<0.01). Histological analysis revealed that the parathyroid glands of Gata3+/− mice failed to enlarge in size to the same extent as in Gata3+/+ mice in response to the low calcium-vitamin D diet and had a reduced Ki-67 proliferation index (0.08 vs 0.16, P<0.01). Analysis of the developing parathyroid glands in 11.5 days post coitum (dpc) mouse embryos revealed that Gata3+/− embryos had smaller parathyroid–thymus primordia compared to Gata3+/+, with fewer cells expressing the parathyroid-specific glial-cell missing 2 (Gcm2) gene, whist Gata3−/− embryos had absent Gcm2 expression and gross defects of the third and fourth pharyngeal pouch development that resulted in absence of the parathyroid–thymus primordia by 12.5 dpc. These data show that Gata3 is critical for the differentiation and subsequent survival of both parathyroid and thymus progenitor cells. Thus, parathyroid agenesis occurs in Gata3−/− mice and haploinsufficiency in Gata3+/− mice is associated with a smaller parathyroid mass, Gcm2 dysregulation, and parathyroid dysfunction. These findings indicate that Gata3 and Gcm2 may form part of a transcriptional cascade that determines parathyroid gland development and parathyroid cell differentiation and proliferation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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