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Departments of Medicine (J.Q., T.L.C.) and Molecular Genetics (E.G.), University of Cincinnati, Cincinnati, Ohio 45267; Division of Molecular Cardiovascular Biology (M.C.C., H.O.), Department of Pathology (D.W.), and Department of Molecular Developmental Biology (C.-Y.K.), Children’s Hospital Medical Center, Cincinnati, Ohio 45229; Department of Oral Pathology (B.L.), The Forsythe Institute and Harvard Dental School, Boston, Massachusetts 02115; and Endocrine Unit (H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Thomas L. Clemens, Ph.D., Division of Endocrinology and Metabolism, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267-0547. E-mail: clementl{at}uc.edu.
PTHrP is a key developmental regulatory protein and a potent vasoactive agent. Previous studies have shown that mice lacking either the Pthrp or the PTH type 1 receptor (Pth1r) gene exhibit severe chondrodysplasia. In addition, in most genetic backgrounds, the receptor null mice die prenatally at midgestation, but the cause of death remains elusive. Here we show the loss of the Pth1r gene in C57BL6 mice leads to massive, abrupt cardiomyocyte death and embryonic lethality between embryonic days (E) E11.5 and E12.5. PTH1R mRNA was abundantly expressed in the developing wild-type mouse heart and cardiomyocytes from E11.5 embryos demonstrated acute increases in cAMP and increased Ca2+oscillations in response to PTHrP-(1–34)NH2. Analyses of more than 300 embryos (E8–E14.5) from C57BL6/PTH1R +/- matings showed that PTH1R-/- mice survived until E11 with no obvious defects in any tissue. By E12, only 10% of the PTH1R-/- embryos survived and all PTH1R null mice were dead by E13. Ultrastructural and histological analysis revealed striking mitochondrial abnormalities at E11.5 and precipitous cardiomyocyte death between E12.0 and E12.5, followed by degenerative changes in the liver and massive necrosis of other tissues. No abnormalities were observed in the yolk sac or placenta implicating the heart degeneration as the primary cause of death. Taken together, these findings indicate that the PTH1R is required for the development of normal cardiomyocyte function.
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