S100a4-Cre–mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: role of pituitary hematopoietic cells in endocrine regulation
Yi Athena Ren, Teresa Monkkonen, Michael T. Lewis, Daniel J. Bernard, Helen C. Christian, Carolina J. Jorgez, Joshua A. Moore, John D. Landua, Haelee M. Chin, Weiqin Chen, Swarnima Singh, Ik Sun Kim, Xiang H.F. Zhang, Yan Xia, Kevin J. Phillips, Harry MacKay, Robert A. Waterland, M. Cecilia Ljungberg, Pradip K. Saha, Sean M. Hartig, Tatiana Fiordelisio Coll, JoAnne S. Richards
Yi Athena Ren, Teresa Monkkonen, Michael T. Lewis, Daniel J. Bernard, Helen C. Christian, Carolina J. Jorgez, Joshua A. Moore, John D. Landua, Haelee M. Chin, Weiqin Chen, Swarnima Singh, Ik Sun Kim, Xiang H.F. Zhang, Yan Xia, Kevin J. Phillips, Harry MacKay, Robert A. Waterland, M. Cecilia Ljungberg, Pradip K. Saha, Sean M. Hartig, Tatiana Fiordelisio Coll, JoAnne S. Richards
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Research Article Endocrinology Reproductive biology

S100a4-Cre–mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: role of pituitary hematopoietic cells in endocrine regulation

Abstract

Hormones produced by the anterior pituitary gland regulate an array of important physiological functions, but the causes of pituitary hormone disorders are not fully understood. Herein we report that genetically engineered mice with deletion of the hedgehog signaling receptor PATCHED1 (Ptch1) by S100a4 promoter–driven Cre recombinase (S100a4-Cre;Ptch1fl/fl mutants) exhibit adult-onset hypogonadotropic hypogonadism and multiple pituitary hormone disorders. During the transition from puberty to adulthood, S100a4-Cre;Ptch1fl/fl mice of both sexes develop hypogonadism coupled with reduced gonadotropin levels. Their pituitary glands also display severe structural and functional abnormalities, as revealed by transmission electron microscopy and expression of key genes regulating pituitary endocrine functions. S100a4-Cre activity in the anterior pituitary gland is restricted to CD45+ cells of hematopoietic origin, including folliculo-stellate cells and other immune cell types, causing sex-specific changes in the expression of genes regulating the local microenvironment of the anterior pituitary. These findings provide in vivo evidence for the importance of pituitary hematopoietic cells in regulating fertility and endocrine function, in particular during sexual maturation and likely through sexually dimorphic mechanisms. These findings support a previously unrecognized role of hematopoietic cells in causing hypogonadotropic hypogonadism and provide inroads into the molecular and cellular basis for pituitary hormone disorders in humans.

Authors

Yi Athena Ren, Teresa Monkkonen, Michael T. Lewis, Daniel J. Bernard, Helen C. Christian, Carolina J. Jorgez, Joshua A. Moore, John D. Landua, Haelee M. Chin, Weiqin Chen, Swarnima Singh, Ik Sun Kim, Xiang H.F. Zhang, Yan Xia, Kevin J. Phillips, Harry MacKay, Robert A. Waterland, M. Cecilia Ljungberg, Pradip K. Saha, Sean M. Hartig, Tatiana Fiordelisio Coll, JoAnne S. Richards

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Figure 6

Adult Ptch1-mutant mice exhibit severe pituitary abnormalities with sexually dimorphic manifestation.

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Adult Ptch1-mutant mice exhibit severe pituitary abnormalities with sexu...
Relative mRNA levels of pituitary endocrine function genes in whole pituitaries of wild-type controls and homozygous Ptch1 mutants at 8 weeks (A), 4 weeks (B, bars of brighter gray and brown colors), and 5 weeks (B, bars of darker grey and brown colors) of age (B). Total RNA was assayed by qPCR and the concentration of each transcript was normalized to that of housekeeping gene Rpl19. Data are presented as fold change of mRNA levels in mutants versus wild-type controls (n ≥ 5). *P < 0.05; **P < 0.01; ***P < 0.001; Student’s t test. (C) Representative images of pituitary morphology at 8 weeks of age. Scale is in units of millimeters. (D) Representative images of transmission electron microscopy on pituitary tissues from control and Ptch1 mutant mice at 8 weeks of age. Endocrine cell types are identified according to their ultrastructural features and labeled with the name of the hormones they produce. The images of gonadotropes are from male mice, and the images of thyrotropes and somatotropes are from female mice. Scale bars: 5 μm and 2 μm (top middle image). (E) Relative mRNA levels of genes in the HH signaling pathway in whole pituitary tissues of wild-type controls and homozygous Ptch1 mutants at 8 weeks of age (n ≥ 5). Total RNA was assayed by qPCR and the concentration of each transcript was normalized to that of housekeeping gene Rpl19. Data are represented as mean ± SD. *P < 0.05; Student’s t test.