Disease relevance of Gcm2

• Here we show that Gcm2-deficient mice lack parathyroid glands and exhibit a biological hypoparathyroidism, identifying Gcm2 as a master regulatory gene of parathyroid gland development [1].
• Superimposed Gcm2 deficiency rescued the perinatal lethality in CasR-deficient mice in association with ablation of the parathyroid glands and correction of the severe hyperparathyroidism [2].

High impact information on Gcm2

• Despite their lack of parathyroid glands, Gcm2-deficient mice have PTH serum levels identical to those of wild-type mice, as do parathyroidectomized wild-type animals [1].
• Unlike PTH receptor-deficient mice, however, Gcm2-deficient mice are viable and fertile, and have only a mildly abnormal bone phenotype [1].
• Thus, Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands [1].
• CasR deficiency was transferred onto the glial cells missing 2-deficient (Gcm2-deficient) background by intercrossing CasR- and Gcm2-deficient mice [2].
• Analysis of the skeleton of 6-week-old homozygous CasR- and Gcm2-deficient mice also failed to identify any essential, nonredundant role for CasR in regulating chondrogenesis or osteogenesis, but further studies are needed to establish the function of CasR in the skeleton [2].

Biological context of Gcm2

• However, the endodermal cells of the thymus/parathyroid rudiments fail to maintain the expression of the parathyroid-specific gene Gcm2 and the thymus-specific gene Foxn1 and subsequently undergo abnormal apoptosis, leading to a complete disappearance of organ primordia by E12 [3].
• In effect, we were able to identify two separate transactivation domains within mGCMb, one carboxyl-terminally adjacent to the DNA-binding domain and the second within the extreme carboxyl terminus [4].

Anatomical context of Gcm2

• In addition, we show that in Eya1(-/-) embryos, the expression of Gcm2 in the 3rd pouch endoderm is undetectable at E10.5, however, the expression of Hox and Pax genes in the pouch endoderm is preserved at E9.5-10 [5].

Other interactions of Gcm2

• The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes [6].
• However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants [6].
• Changes in the distribution of Bmp4 and Gcm2 in the third pouch endoderm and subsequent organ phenotypes in Shh-/- mutants suggested that exclusion of Shh from the third pouch is required for dorsal-ventral patterning and for parathyroid specification and organogenesis [7].
• Furthermore, pulse-chase experiments proved that the mGCMb protein has a half-life approximately four times shorter than mGCMa [4].

References