Cells responding to hedgehog signaling contribute to the theca of ovarian follicles

in Reproduction
Authors:
Robert G Cowan Department of Animal Science, Cornell University, Ithaca, New York, USA

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Susan M Quirk Department of Animal Science, Cornell University, Ithaca, New York, USA

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Correspondence should be addressed to S M Quirk; Email: smq1@cornell.edu
DOI:
https://doi.org/10.1530/REP-20-0471
Volume/Issue:
Volume 161: Issue 4
Page Range:
437–448
Article Type:
Research Article
Online Publication Date:
Apr 2021
Copyright:
© 2021 Society for Reproduction and Fertility 2021
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Cell-fate mapping was used to identify cells that respond to the hedgehog (HH) signaling pathway and that are incorporated into the theca cell layer during ovarian follicle development. Expression of Gli1 is increased by HH signaling and can be used as a marker of cells responsive to HH in reporter mice. In transgenic Gli1ERcre/tdT mice, injection of tamoxifen (TAM) induces cre-mediated recombination and expression of td tomato (tdT) which leads to permanent fluorescent marking of cells expressing Gli1 and their progeny. The identity of tdT-positive cells was determined by co-staining ovaries for endothelial cells (CD31), pericytes (CSPG4), vascular smooth muscle cells (VSMC; smooth muscle actin) and steroidogenic cells (cytochrome P450 17A1). Gli1ERcre/tdT mice were injected with TAM on the day of birth. Cells positive for tdT in 2-day-old mice were identified as pericytes, located primarily in the medulla of the ovary in close proximity to endothelial cells. In both prepubertal mice and adult mice treated with equine chorionic gonadotropin to induce the formation of preovulatory follicles, tdT-positive cells were located within the theca cell layer and were identified as pericytes, VSMC and steroidogenic theca cells. Granulosa cells are known to express two HH ligands, Indian HH and desert HH (DHH). In DHHcre/tdT reporter mice, endothelial cells were marked as tdT-positive indicating that endothelial cells, in addition to granulosa cells, express Dhh in the ovary. These findings suggest that HH signaling may stimulate the development of the vasculature along with steroidogenic capacity of the theca layer during follicle development.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Aad PY, Echternkamp SE, Sypherd DD, Schreiber NB & Spicer LJ 2012 The hedgehog system in ovarian follicles of cattle selected for twin ovulations and births: evidence of a link between the IGF and hedgehog systems. Biology of Reproduction 87 79. (https://doi.org/10.1095/biolreprod.111.096735)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ahn S & Joyner AL 2004 Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell 118 505–516. (https://doi.org/10.1016/j.cell.2004.07.023)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Armulik A, Abramsson A & Betsholtz C 2005 Endothelial/pericyte interactions. Circulation Research 97 512–523. (https://doi.org/10.1161/01.RES.0000182903.16652.d7)

  • Astorga J & Carlsson P 2007 Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4. Development 134 3753–3761. (https://doi.org/10.1242/dev.004432)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bai CB, Auerbach W, Lee JS, Stephen D & Joyner AL 2002 Gli2 , but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129 4753–4761.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bassett DL 1943 The changes in the vascular pattern of the ovary of the albino rat during the estrous cycle. American Journal of Anatomy 73 251–291. (https://doi.org/10.1002/aja.1000730206)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bicknell R & Harris AL 2004 Novel angiogenic signaling pathways and vascular targets. Annual Review of Pharmacology and Toxicology 44 219–238. (https://doi.org/10.1146/annurev.pharmtox.44.101802.121650)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bitgood MJ & McMahon AP 1995 Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Developmental Biology 172 126–138. (https://doi.org/10.1006/dbio.1995.0010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bitgood MJ, Shen L & McMahon AP 1996 Sertoli cell signaling by desert hedgehog regulates the male germline. Current Biology 6 298–304. (https://doi.org/10.1016/s0960-9822(0200480-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Byrd N & Grabel L 2004 Hedgehog signaling in murine vasculogenesis and angiogenesis. Trends in Cardiovascular Medicine 14 308–313. (https://doi.org/10.1016/j.tcm.2004.09.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caradu C, Couffinhal T, Chapouly C, Guimbal S, Hollier PL, Ducasse E, Bura-Riviere A, Dubois M, Gadeau AP & Renault MA 2018 Restoring endothelial function by targeting desert hedgehog downstream of Klf2 improves critical limb ischemia in adults. Circulation Research 123 1053–1065. (https://doi.org/10.1161/CIRCRESAHA.118.313177)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chapouly C, Guimbal S, Hollier PL & Renault MA 2019 Role of hedgehog signaling in vasculature development, differentiation, and maintenance. International Journal of Molecular Sciences 20 3076. (https://doi.org/10.3390/ijms20123076)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Donadeu FX, Fahiminiya S, Esteves CL, Nadaf J, Miedzinska K, McNeilly AS, Waddington D & Gerard N 2014 Transcriptome profiling of granulosa and theca cells during dominant follicle development in the horse. Biology of Reproduction 91 111. (https://doi.org/10.1095/biolreprod.114.118943)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dyer MA, Farrington SM, Mohn D, Munday JR & Baron MH 2001 Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128 1717–1730.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Feng Y, Cui P, Lu X, Hsueh B, Moller Billig F, Zarnescu Yanez L, Tomer R, Boerboom D, Carmeliet P & Deisseroth K et al.2017 CLARITY reveals dynamics of ovarian follicular architecture and vasculature in three-dimensions. Scientific Reports 7 44810. (https://doi.org/10.1038/srep44810)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fraser HM 2006 Regulation of the ovarian follicular vasculature. Reproductive Biology and Endocrinology 4 18. (https://doi.org/10.1186/1477-7827-4-18)

  • Hirshfield AN 1991 Theca cells may be present at the outset of follicular growth. Biology of Reproduction 44 1157–1162. (https://doi.org/10.1095/biolreprod44.6.1157)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Honda A, Hirose M, Hara K, Matoba S, Inoue K, Miki H, Hiura H, Kanatsu-Shinohara M, Kanai Y & Kono T et al.2007 Isolation, characterization, and in vitro and in vivo differentiation of putative thecal stem cells. PNAS 104 12389–12394. (https://doi.org/10.1073/pnas.0703787104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jaegle M, Ghazvini M, Mandemakers W, Piirsoo M, Driegen S, Levavasseur F, Raghoenath S, Grosveld F & Meijer D 2003 The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes and Development 17 1380–1391. (https://doi.org/10.1101/gad.258203)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kanzaki H, Okamura H, Okuda Y, Takenaka A, Morimoto K & Nishimura T 1982 Scanning electron microscopic study of rabbit ovarian follicle microvasculature using resin injection-corrosion casts. Journal of Anatomy 134 697–704.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL & Humphreys BD 2015 Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16 51–66. (https://doi.org/10.1016/j.stem.2014.11.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lamont RE, Vu W, Carter AD, Serluca FC, MacRae CA & Childs SJ 2010 Hedgehog signaling via angiopoietin1 is required for developmental vascular stability. Mechanisms of Development 127 159–168. (https://doi.org/10.1016/j.mod.2010.02.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lindeboom F, Gillemans N, Karis A, Jaegle M, Meijer D, Grosveld F & Philipsen S 2003 A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse. Nucleic Acids Research 31 5405–5412. (https://doi.org/10.1093/nar/gkg723)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu C, Peng J, Matzuk MM & Yao HH 2015 Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nature Communications 6 6934. (https://doi.org/10.1038/ncomms7934)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu C, Rodriguez KF, Brown PR & Yao HH 2018 Reproductive, physiological, and molecular outcomes in female mice deficient in Dhh and Ihh. Endocrinology 159 2563–2575. (https://doi.org/10.1210/en.2018-00095)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Macchiarelli G, Jiang JY, Nottola SA & Sato E 2006 Morphological patterns of angiogenesis in ovarian follicle capillary networks. A scanning electron microscopy study of corrosion cast. Microscopy Research and Technique 69 459–468. (https://doi.org/10.1002/jemt.20305)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McFee RM & Cupp AS 2013 Vascular contributions to early ovarian development: potential roles of VEGFA isoforms. Reproduction, Fertility, and Development 25 333–342. (https://doi.org/10.1071/RD12134)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Migone FF, Cowan RG, Williams RM, Gorse KJ, Zipfel WR & Quirk SM 2016 In vivo imaging reveals an essential role of vasoconstriction in rupture of the ovarian follicle at ovulation. PNAS 113 2294–2299. (https://doi.org/10.1073/pnas.1512304113)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mogha A, Benesh AE, Patra C, Engel FB, Schoneberg T, Liebscher I & Monk KR 2013 Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. Journal of Neuroscience 33 17976–17985. (https://doi.org/10.1523/JNEUROSCI.1809-13.2013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moran CM, Salanga MC & Krieg PA 2011 Hedgehog signaling regulates size of the dorsal aortae and density of the plexus during avian vascular development. Developmental Dynamics 240 1354–1364. (https://doi.org/10.1002/dvdy.22600)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morrow D, Cullen JP, Liu W, Guha S, Sweeney C, Birney YA, Collins N, Walls D, Redmond EM & Cahill PA 2009 Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A. Arteriosclerosis, Thrombosis, and Vascular Biology 29 1112–1118. (https://doi.org/10.1161/ATVBAHA.109.186890)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nielsen CM & Dymecki SM 2010 Sonic hedgehog is required for vascular outgrowth in the hindbrain choroid plexus. Developmental Biology 340 430–437. (https://doi.org/10.1016/j.ydbio.2010.01.032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky RB, Shapiro R, Taylor FR, Baker DP & Asahara T et al.2001 The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nature Medicine 7 706–711. (https://doi.org/10.1038/89083)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pola R, Ling LE, Aprahamian TR, Barban E, Bosch-Marce M, Curry C, Corbley M, Kearney M, Isner JM & Losordo DW 2003 Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia. Circulation 108 479–485. (https://doi.org/10.1161/01.CIR.0000080338.60981.FA)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ren Y, Cowan RG, Harman RM & Quirk SM 2009 Dominant activation of the hedgehog signaling pathway in the ovary alters theca development and prevents ovulation. Molecular Endocrinology 23 711–723. (https://doi.org/10.1210/me.2008-0391)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ren Y, Cowan RG, Migone FF & Quirk SM 2012 Overactivation of hedgehog signaling alters development of the ovarian vasculature in mice. Biology of Reproduction 86 174. (https://doi.org/10.1095/biolreprod.112.099176)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Russell MC, Cowan RG, Harman RM, Walker AL & Quirk SM 2007 The hedgehog signaling pathway in the mouse ovary. Biology of Reproduction 77 226–236. (https://doi.org/10.1095/biolreprod.106.053629)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S & Schmid B et al.2012 Fiji: an open-source platform for biological-image analysis. Nature Methods 9 676–682. (https://doi.org/10.1038/nmeth.2019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schmid B, Schindelin J, Cardona A, Longair M & Heisenberg M 2010 A high-level 3D visualization API for Java and ImageJ. BMC Bioinformatics 11 274. (https://doi.org/10.1186/1471-2105-11-274)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schneider CA, Rasband WS & Eliceiri KW 2012 NIH Image to ImageJ: 25 years of image analysis. Nature Methods 9 671–675. (https://doi.org/10.1038/nmeth.2089)

  • Spicer LJ, Sudo S, Aad PY, Wang LS, Chun SY, Ben-Shlomo I, Klein C & Hsueh AJW 2009 The hedgehog-patched signaling pathway and function in the mammalian ovary: a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells. Reproduction 138 329–339. (https://doi.org/10.1530/REP-08-0317)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Swift MR & Weinstein BM 2009 Arterial-venous specification during development. Circulation Research 104 576–588. (https://doi.org/10.1161/CIRCRESAHA.108.188805)

  • Teixeira J, Maheswaran S & Donahoe PK 2001 Mullerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications. Endocrine Reviews 22 657–674. (https://doi.org/10.1210/edrv.22.5.0445)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van Tuyl M, Groenman F, Wang J, Kuliszewski M, Liu J, Tibboel D & Post M 2007 Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs. Developmental Biology 303 514–526. (https://doi.org/10.1016/j.ydbio.2006.11.029)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Visser JA, Schipper I, Laven JS & Themmen AP 2012 Anti-Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nature Reviews: Endocrinology 8 331–341. (https://doi.org/10.1038/nrendo.2011.224)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vokes SA, Yatskievych TA, Heimark RL, McMahon J, McMahon AP, Antin PB & Krieg PA 2004 Hedgehog signaling is essential for endothelial tube formation during vasculogenesis. Development 131 4371–4380. (https://doi.org/10.1242/dev.01304)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • White AC, Lavine KJ & Ornitz DM 2007 FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. Development 134 3743–3752. (https://doi.org/10.1242/dev.004879)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wijgerde M, Ooms M, Hoogerbrugge JW & Grootegoed JA 2005 Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog induce target gene expression in developing theca cells. Endocrinology 146 3558–3566. (https://doi.org/10.1210/en.2005-0311)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu F, Zhang Y, Sun B, McMahon AP & Wang Y 2017 Hedgehog signaling: from basic biology to cancer therapy. Cell Chemical Biology 24 252–280. (https://doi.org/10.1016/j.chembiol.2017.02.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao H, Feng J, Seidel K, Shi S, Klein O, Sharpe P & Chai Y 2014 Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14 160–173. (https://doi.org/10.1016/j.stem.2013.12.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zheng W, Zhang H, Gorre N, Risal S, Shen Y & Liu K 2014 Two classes of ovarian primordial follicles exhibit distinct developmental dynamics and physiological functions. Human Molecular Genetics 23 920–928. (https://doi.org/10.1093/hmg/ddt486)

    • PubMed
    • Search Google Scholar
    • Export Citation