1. Department of Molecular and Human Genetics, Program of Developmental Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA
2. Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
3. Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena , California 91125, USA
4. Department of Trauma Surgery, Hamburg University, Martinistrasse 52, 20246 Hamburg, Germany
5. St. Vincent's Institute of Medical Research , 9 Princes Street, Fitzroy 3065, Melbourne , Victoria, Australia
6. These authors contributed equally to this work

Correspondence to: Gerard Karsenty¹ Correspondence and requests for materials should be addressed to G.K. (e-mail: Email: karsenty@bcm.tmc.edu).

Abstract

The parathyroid glands are the only known source of circulating parathyroid hormone (PTH), which initiates an endocrine cascade that regulates serum calcium concentration¹. Glial cells missing2 (Gcm2), a mouse homologue of Drosophila Gcm, is the only transcription factor whose expression is restricted to the parathyroid glands^{2, 3, 4, 5}. 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. Unlike PTH receptor-deficient mice, however, Gcm2-deficient mice are viable and fertile, and have only a mildly abnormal bone phenotype. 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. Expression and ablation studies identified the thymus, where Gcm1, another Gcm homologue, is expressed, as the additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. We propose that this backup mechanism may be a general feature of endocrine regulation.