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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 7

Expression of S100a4-Cre is restricted to CD45+ cells, including FS cells, in the anterior pituitary and leads to malfunction of these cells.

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Expression of S100a4-Cre is restricted to CD45+ cells, including FS cell...
(A) Representative images of IF staining for GFP in the anterior pituitary of S100a4-Cre;mTmG reporter control mice. RBC, red blood cell. Scale bars: 200 μm and 20 μm. (B) Representative images of transmission electron microscopy (TEM) of immunogold labeling of GFP on pituitary tissue sections from S100a4-Cre;mTmG reporter mice at 8 weeks of age. Arrows point to immunogold signals. FS, folliculo-stellate cell; EC, endothelial cell. Scale bars: 200 nm (top panels) and 500 nm (bottom panels). (C) The percentage of CD45-positive cells among GFP-positive cells in the pituitaries of S100a4-Cre;mTmG reporter control mice analyzed by flow cytometry. The image represents results from 4 independent samples. (D) Representative images of TEM of FS cells in control and Ptch1-mutant mice. FS cells are identified according to their ultrastructural features. Scale bar: 10 μm. (E) Relative mRNA levels of genes involved in the pituitary microenvironment 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 the housekeeping gene Rpl19. Data are represented as mean ± SD. *P < 0.05; Student’s t test. All data are from mice at 8 weeks of age.

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