Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update. Richards JS et al. (2019) The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure in women. Specifically, we will cover the following: (1) mouse models that have led to discovery of the derivation of two precursor populations of theca cells in the embryonic gonad; (2) the key roles of the oocyte-derived factor growth differentiation factor 9 on the hedgehog (HH) signaling pathway and theca cell functions; and (3) the impact of the HH pathway on both the specification of theca endocrine cells and theca fibroblast and smooth muscle cells in developing follicles. We will also discuss the following: (1) other signaling pathways that impact the differentiation of theca cells, not only luteinizing hormone but also insulinlike 3, bone morphogenic proteins, the circadian clock genes, androgens, and estrogens; and (2) theca-associated vascular, immune, and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth. Lastly, we will integrate what is known about theca cells from mouse models, human-derived theca cell lines from patients who have PCOS and patients who do not have PCOS, and microarray analyses of human and bovine theca to understand what pathways and factors contribute to follicle growth as well as to the abnormal function of theca.////////////////// GDF9 (oocyte)-hedgehog 9granulosa)-smoothern and patched (theca). This gene is a thecal cell marker.
NCBI Summary:
The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Steroid metabolism, Oocyte maturation, Early embryo development
Comment
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. Spicer L et al. The expression of hedgehog (Hh) genes, their receptor, and the co-receptor in mice, rat and bovine ovaries were investigated. Reverse transcription-polymerase chain reaction (RT-PCR) of ovarian transcripts in mice showed amplification of transcripts for Indian (Ihh) and Desert (Dhh) hedgehog, Patched 1 (Ptch1), and Smoothened (Smo) genes. Semi-quantitative RT-PCR and Northern blot analyses showed that whole ovarian Ihh and Dhh transcripts were less 4-24 h after hCG versus 0-48 h after PMSG treatment in mice, whereas mouse Ptch1 and Smo transcripts were expressed throughout the gonadotropin treatments. Quantitative real-time RT-PCR (qRT-PCR) revealed the expression of the hedgehog-Patched signaling system with Ihh mRNA abundance in granulosa cells greater whereas Smo and Ptch1 mRNA abundance less in theca cells of small versus large follicles of cattle. In cultured rat and bovine theca-interstitial cells, qRT-PCR analyses revealed abundance of Gli1 and Ptch1 mRNAs were increased (P < 0.05) with SHH treatment. Additional studies using cultured bovine theca cells indicated that SHH induces proliferation and androstenedione production. IGF1 decreased Ihh mRNA abundance in bovine granulosa cells. The expression and regulation of Ihh transcripts in granulosa cells and Ptch1 mRNA in theca cells suggests a potential paracrine role of this system in bovine follicular development. These studies illustrate for the first time hedgehog activation of Gli1 transcriptional factor in theca cells and its stimulation of theca cell proliferation and androgen biosynthesis.
Sonic hedgehog promotes porcine oocyte maturation and early embryo development. Nguyen NT et al. In the present study, we investigated the effects of the Sonic hedgehog (Shh) protein on porcine oocyte maturation and early embryo development. Immunohistochemistry showed activation of Shh signalling in cumulus-oocyte complexes (COCs), as reflected by Patched (Ptc), Smoothened (Smo) and Gli1 expression in oocytes, cumulus cells and granulosa cells, particularly those of small follicles (<2 mm in diameter). Western blot analysis showed Smo expression in COCs and in denuded oocytes derived from small and medium (3-7 mm)-sized follicles. Small follicles contained the highest concentration of Shh in follicular fluid compared with medium-sized and large (>7 mm in diameter) follicles. Supplementation with Shh (0.5 or 1 mug mL(-1)) enhanced oocyte maturation compared with the control group (92.4% and 90.4% v. 81.9%, respectively; P < 0.05). This effect was reversed by the simultaneous addition of cyclopamine (1-2 mum), an Shh inhibitor. Similar to intact COCs, denuded COCs showed enhanced maturation following Shh supplementation. Furthermore, cyclin B1 content, extracellular signal-regulated kinase 1/2 phosphorylation, intracellular calcium release, blastocyst rate and total cell numbers were greater (P < 0.05) in oocytes matured in the presence of 0.5 and 1 mug mL(-1) Shh compared with control oocytes. The findings of the present study provide the first evidence that the Shh signalling pathway is active, or at least partially activated, in the porcine ovary and is likely to promote oocyte cytoplasmic and nuclear maturation, as well as subsequent in vitro development, although the underlying mechanisms remain to be elucidated.
Expression regulated by
Comment
Ovarian localization
Theca
Comment
Wijgerde M, et al reported hedgehog signaling in mouse ovary: Ihh and Dhh from granulosa cells induce target gene expression in developing theca cells.
Follicle development in the mammalian ovary requires interactions between the oocyte, granulosa cells, and theca cells, co-ordinating gametogenesis and steroidogenesis. Here, we show that granulosa cells of growing follicles in mouse ovary act as a source of hedgehog signaling. Expression of indian hedgehog (Ihh) and desert hedgehog (Dhh) mRNAs initiates in granulosa cells at the primary follicle stage, and we find induced expression of the hedgehog target genes Ptch1 and Gli1, in the surrounding pre-theca cell compartment. Cyclopamine, a highly specific hedgehog signaling antagonist, inhibits this induced expression of target genes, in cultured neonatal mouse ovaries. The theca cell compartment remains a target of hedgehog signaling throughout follicle development, showing induced expression of the hedgehog target genes Ptch1, Ptch2, Hip1, and Gli1. In peri-ovulatory follicles, a dynamic synchrony between loss of hedgehog expression and loss of induced target gene expression is observed. Oocytes are unable to respond to hedgehog, since they lack expression of the essential signal transducer Smo (smoothened). The present results point to a prominent role of hedgehog signaling in the communication between granulosa cells and developing theca cells.
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: targeted overexpression fertility: subfertile Comment: Dominant activation of the hedgehog signaling pathway alters development of the female reproductive tract. Migone FF et al. The role of hedgehog (HH) signaling in reproductive tract development was studied in mice in which a dominant active allele of the signal transducer smoothened (SmoM2) was conditionally expressed in the Mllerian duct and ovary. Mutant females are infertile, primarily because they fail to ovulate. Levels of mRNA for targets of HH signaling, Gli1, Ptch1 and Hhip, were elevated in reproductive tracts of 24-day old mutant mice, confirming over-activation of HH signaling. The tracts of mutant mice developed abnormally. The uterine luminal epithelium had a simple columnar morphology in control mice, but in mutants contained stratified squamous cells typical of the cervix and vagina. In mutant mice, the number of uterine glands were reduced and the oviducts were not coiled. Expression of genes within the Hox and Wnt families that regulate patterning of the reproductive tract were altered. Hoxa13, which is normally expressed primarily in the vagina and cervix, was expressed at 12-fold higher levels in the uterus of mutant mice compared to controls. Wnt5a, which is required for development of the cervix and vagina and postnatal differentiation of the uterus, was expressed at higher levels in the oviduct and uterus of mutant mice compared to controls. Mating mutant females with fertile or vasectomized males induced a severe inflammatory response in the tract. In summary, over-activation of HH signaling causes aberrant development of the reproductive tract. The phenotype observed could be mediated by ectopic expression of Hoxa13 in the uterus and elevated levels of Wnt5a in the oviducts and uterus. 2011 Wiley-Liss, Inc.
Species: mouse
Mutation name: type: null mutation fertility: infertile - non-ovarian defect Comment: Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility. Rennert C et al. (2017) The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.//////////////////