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 25, 2019; First 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 4

S100a4-Cre is expressed in CD45+ cells in the gonads.

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S100a4-Cre is expressed in CD45+ cells in the gonads. (A) Representativ...
(A) Representative images of IF staining of GFP and S100A4 in the ovaries of reporter controls and homozygous Ptch1 mutants (both express GFP driven by S100a4-Cre). CL, corpus luteum; F, follicle; AF, atretic follicle. Scale bars: 200 μm (upper panels) and 100 μm (lower panels). (B) Representative images of IF staining of GFP with vimentin or ACTA2 in the ovaries of reporter controls and homozygous Ptch1 mutants. Scale bars: 40 μm (upper panels) and 75 μm (lower panels). (C) Representative images of IF staining of GFP and IHC staining of CD45 on adjacent serial sections of ovaries from reporter controls and homozygous Ptch1 mutants. Scale bar: 100 μm. (D) The percentage of CD45-positive cells among GFP-positive cells in the ovaries of S100a4-Cre;mTmG reporter control mice analyzed by flow cytometry. The image represents results from 3 independent samples, each of which contained dispersed ovarian cells pooled from 4 females. (E) Representative images of Xgal signal in testes of Ptch1-Xgal mice, as well as S100A4 and GFP staining in the testis of S100a4-Cre;mTmG reporter control mice. Arrows point to cells positive for GFP alone (green), S100A4 alone (red), or for both GFP and S100A4 (white). Scale bars: 50 μm and 20 μm (bottom right). (F) Representative images of IF staining of GFP and CYP17A1 in testes of S100a4-Cre;mTmG reporter control mice. The right panel is a zoomed-in view of the same tissue and staining as the left panel. Scale bars: 50 μm (left image) and 20 μm (right image).