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

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 3

Hypogonadism in Ptch1-mutant mice develops during the puberty-to-adult transition.

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Hypogonadism in Ptch1-mutant mice develops during the puberty-to-adult t...
(A) Representative images of wild-type control and homozygous Ptch1-mutant female ovarian histology with H&E staining at 5 weeks of age. CL, corpus luteum; AF, antral follicle. Scale bar: 400 μm. (B) Numbers of cumulus-oocyte complexes (COCs) ovulated into the oviduct and counted at 20 hours after hCG during a superovulation stimulation in wild-type control, heterozygous, and homozygous Ptch1-mutant females at 22 days of age (n = 9, wild-type; n = 4, heterozygous mutant; and n = 5, homozygous mutant). (C) Representative images of wild-type control and homozygous Ptch1-mutant female ovarian histology with H&E staining at 8 weeks of age with superovulation stimulation (20 hours after hCG). Scale bar: 400 μm, 200 μm (insets) (D) Numbers of COCs ovulated into the oviduct and counted at 20 hours after hCG during a superovulation stimulation in wild-type control, heterozygous, and homozygous Ptch1-mutant females at 8 weeks of age (n = 6, wild-type; n = 5, heterozygous mutant; and n = 5, homozygous mutant). **P < 0.01; ***P < 0.001; one-way ANOVA followed by SNK post hoc test.