Genetic analysis of the role of Gcm2 gene in mouse embryonic development
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The molecular mechanism of parathyroid organogenesis is poorly understood. The mouse rdGcm2 gene was found to be expressed predominantly at the anterior/dorsal side of the 3 pouch endoderm and subsequently in the parathyroid domain of the parathyroid/thymus common primordium. The Gcm2 null mutation causes loss of parathyroids in mouse, indicating that Gcm2 is an important regulator gene for parathyroid organogenesis. Based on this observation, Gcm2 has been thought to be a cell fate determinant, like its orthologous Drosophila Gcm genes, to specify the parathyroid domain in the 3 pouch. Besides its function in parathyroid organogenesis, low level expression of Gcm2 has been detected in the mouse brain and otic region, although its function here is unknown. In my doctoral study, I genetically dissected how Gcm2 functions in parathyroid organogenesis and whether Gcm2 has a role in the development of other organs. My loss-of-function studies in the Gcm2 mutants showed that the specification of the parathyroid/thymus was normal, but that the parathyroid domain did not differentiate properly and subsequently underwent apoptosis. This suggests that Gcm2 is required for the differentiation and subsequent survival of parathyroid precursor cells, but not for the specification of the parathyroid domain. It has been proposed that parathyroid hormone (PTH) expression in the thymus is a backup mechanism for the parathyroids in Gcm2 mutants. Interestingly, we identified two cellular sources for thymic PTH: misplaced parathyroid cells and medullary thymic epithelial cells (mTECs). PTH expression in the former source is regulated by Gcm2, whereas mTECs express PTH in a Gcm2-independent way. Our further studies showed that mTEC-derived PTH did not contribute to serum PTH, suggesting that the lethality of Gcm2 mutants may not be related to the reduction of serum PTH levels but is caused by non-parathyroid defects. To further study Gcm2 function, we ectopically expressed Gcm2 in other tissues. Mice with ubiquitous Gcm2 expression displayed multiple abnormal phenotypes, including defective eyelid and inner ear structures, and neonatal lethality. Gcm2 has been shown to be expressed in the brain and otic region. Thus our data suggest that Gcm2 may have a role in the development of other organs.