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S100a4-Cre–mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: role of pituitary hematopoietic cells in endocrine regulation
Yi Athena Ren, … , Tatiana Fiordelisio Coll, JoAnne S. Richards
Yi Athena Ren, … , Tatiana Fiordelisio Coll, JoAnne S. Richards
Published July 2, 2019
Citation Information: JCI Insight. 2019;4(14):e126325. https://doi.org/10.1172/jci.insight.126325.
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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

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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 2

Homozygous ablation of Ptch1 with S100a4-Cre leads to hypogonadism in male mice.

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Homozygous ablation of Ptch1 with S100a4-Cre leads to hypogonadism in ma...
(A) Representative images of wild-type control and homozygous Ptch1-mutant male reproductive tissue morphology, including seminal vesicles (SV), epididymis (E), and testes (T). (B) Serum concentration of testosterone in control and homozygous Ptch1-mutant male mice (n = 5). N.S., not significant. (C) Relative mRNA levels of testis-function genes in whole testes from wild-type control and homozygous Ptch1 mutants (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. (D) Representative images of wild-type control and homozygous Ptch1-mutant seminiferous tubules with PAS staining. Scale bars: 100 μm (lower-magnification images) and 25 μm (higher-magnification images). Asterisk: impaired hierarchical organization; arrow: multinucleated cells; arrowheads: vacuoles. All data are from mice at 8 weeks of age.

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