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  1. Article ; Online: Steroidogenic factor 1 (SF-1;

    Hughes, Camilla H K / Smith, Olivia E / Meinsohn, Marie-Charlotte / Brunelle, Mylène / Gévry, Nicolas / Murphy, Bruce D

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 32, Page(s) e2220849120

    Abstract: The ovarian follicle reserve, formed pre- or perinatally, comprises all oocytes for lifetime reproduction. Depletion of this reserve results in infertility. Steroidogenic factor 1 (SF-1; ...

    Abstract The ovarian follicle reserve, formed pre- or perinatally, comprises all oocytes for lifetime reproduction. Depletion of this reserve results in infertility. Steroidogenic factor 1 (SF-1;
    MeSH term(s) Pregnancy ; Female ; Humans ; Steroidogenic Factor 1/genetics ; Steroidogenic Factor 1/metabolism ; Ovarian Reserve/genetics ; Ovarian Follicle/metabolism ; Ovary/metabolism ; Granulosa Cells/metabolism
    Chemical Substances Steroidogenic Factor 1
    Language English
    Publishing date 2023-07-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2220849120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction.

    Meinsohn, Marie-Charlotte / Smith, Olivia E / Bertolin, Kalyne / Murphy, Bruce D

    Physiological reviews

    2019  Volume 99, Issue 2, Page(s) 1249–1279

    Abstract: Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 ( ... ...

    Abstract Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
    MeSH term(s) Animals ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Endometriosis/metabolism ; Endometriosis/pathology ; Female ; Gene Expression Regulation ; Humans ; Leydig Cell Tumor/metabolism ; Leydig Cell Tumor/pathology ; Ligands ; Male ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Pregnancy ; Protein Conformation ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Reproduction ; Signal Transduction ; Steroidogenic Factor 1/chemistry ; Steroidogenic Factor 1/genetics ; Steroidogenic Factor 1/metabolism ; Structure-Activity Relationship ; Testicular Neoplasms/metabolism ; Testicular Neoplasms/pathology
    Chemical Substances Ligands ; NR5A1 protein, human ; NR5A2 protein, human ; Receptors, Cytoplasmic and Nuclear ; Steroidogenic Factor 1
    Language English
    Publishing date 2019-02-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 209902-0
    ISSN 1522-1210 ; 0031-9333
    ISSN (online) 1522-1210
    ISSN 0031-9333
    DOI 10.1152/physrev.00019.2018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation.

    Meinsohn, Marie-Charlotte / Hughes, Camilla H K / Estienne, Anthony / Saatcioglu, Hatice D / Pépin, David / Duggavathi, Raj / Murphy, Bruce D

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 1079

    Abstract: Liver receptor homolog-1 (NR5A2) is expressed specifically in granulosa cells of developing ovarian follicles where it regulates the late stages of follicle development and ovulation. To establish its effects earlier in the trajectory of follicular ... ...

    Abstract Liver receptor homolog-1 (NR5A2) is expressed specifically in granulosa cells of developing ovarian follicles where it regulates the late stages of follicle development and ovulation. To establish its effects earlier in the trajectory of follicular development, NR5A2 was depleted from granulosa cells of murine primordial and primary follicles. Follicle populations were enumerated in neonates at postnatal day 4 (PND4) coinciding with the end of the formation of the primordial follicle pool. The frequency of primordial follicles in PND4 conditional knockout (cKO) ovaries was greater and primary follicles were substantially fewer relative to control (CON) counterparts. Ten-day in vitro culture of PND4 ovaries recapitulated in vivo findings and indicated that CON mice developed primary follicles in the ovarian medulla to a greater extent than did cKO animals. Two subsets of primordial follicles were observed in wildtype ovaries: one that expressed NR5A2 and the second in which the transcript was absent. Neither expressed the mitotic marker. KI-67, indicating their developmental quiescence. RNA sequencing on PND4 demonstrated that loss of NR5A2 induced changes in 432 transcripts, including quiescence markers, inhibitors of follicle activation, and regulators of cellular migration and epithelial-to-mesenchymal transition. These experiments suggest that NR5A2 expression poises primordial follicles for entry into the developing pool.
    MeSH term(s) Animals ; Female ; Gene Deletion ; Gene Expression ; Mice ; Mice, Inbred C57BL ; Ovarian Follicle/cytology ; Ovarian Follicle/metabolism ; Ovarian Follicle/ultrastructure ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Transcriptome
    Chemical Substances Nr5a2 protein, mouse ; Receptors, Cytoplasmic and Nuclear
    Language English
    Publishing date 2021-01-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-80178-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A single-cell atlas of the cycling murine ovary.

    Morris, Mary E / Meinsohn, Marie-Charlotte / Chauvin, Maeva / Saatcioglu, Hatice D / Kashiwagi, Aki / Sicher, Natalie A / Nguyen, Ngoc / Yuan, Selena / Stavely, Rhian / Hyun, Minsuk / Donahoe, Patricia K / Sabatini, Bernardo L / Pépin, David

    eLife

    2022  Volume 11

    Abstract: The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of ... ...

    Abstract The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle and the paracrine factors that help coordinate this process. Herein, we used single-cell RNA sequencing to evaluate the transcriptome of >34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states.
    MeSH term(s) Animals ; Estrous Cycle/physiology ; Female ; Mice ; Ovarian Follicle/physiology ; Ovary ; Ovulation/physiology ; Pelvis
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.77239
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  5. Article ; Online: A screen of repurposed drugs identifies AMHR2/MISR2 agonists as potential contraceptives.

    Li, Yi / Wei, Lina / Meinsohn, Marie-Charlotte / Suliman, Rana / Chauvin, Maeva / Berstler, Jim / Hartland, Kate / Jensen, Mark M / Sicher, Natalie A / Nagykery, Nicholas / Donahoe, Patricia K / Pepin, David

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 15, Page(s) e2122512119

    Abstract: We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a ... ...

    Abstract We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a promising druggable target for the modulation of female reproduction with a mechanism of action distinct from steroidal contraceptives. We designed an in vitro platform to screen and validate small molecules that can activate MISR2 signaling and suppress ovarian folliculogenesis. Using a bone morphogenesis protein (BMP)–response element luciferase reporter cell–based assay, we screened 5,440 compounds from a repurposed drug library. Positive hits in this screen were tested for specificity and potency in luciferase dose–response assays, and biological activity was tested in ex vivo Mullerian duct regression bioassays. Selected candidates were further evaluated in ex vivo follicle/ovary culture assays and in vivo in mice and rats. Here, we report that SP600125, CYC-116, gandotinib, and ruxolitinib can specifically inhibit primordial follicle activation and repress folliculogenesis by stimulating the MISR2 pathway.
    MeSH term(s) Animals ; Anthracenes/chemistry ; Anthracenes/pharmacology ; Contraceptive Agents/chemistry ; Contraceptive Agents/pharmacology ; Drug Evaluation, Preclinical ; Drug Repositioning ; Female ; Humans ; Mice ; Nitriles/chemistry ; Nitriles/pharmacology ; Ovarian Follicle/drug effects ; Ovarian Follicle/growth & development ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Rats ; Receptors, Peptide/agonists ; Receptors, Transforming Growth Factor beta/agonists ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Thiazoles/chemistry ; Thiazoles/pharmacology
    Chemical Substances 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine ; Anthracenes ; Contraceptive Agents ; Nitriles ; Pyrazoles ; Pyrimidines ; Receptors, Peptide ; Receptors, Transforming Growth Factor beta ; Small Molecule Libraries ; Thiazoles ; anti-Mullerian hormone receptor ; pyrazolanthrone (1TW30Y2766) ; ruxolitinib (82S8X8XX8H)
    Language English
    Publishing date 2022-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2122512119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Sperm-borne glutathione-S-transferase omega 2 accelerates the nuclear decondensation of spermatozoa during fertilization in mice†.

    Hamilton, Lauren E / Suzuki, Joao / Aguila, Luis / Meinsohn, Marie-Charlotte / Smith, Olivia E / Protopapas, Nicole / Xu, Wei / Sutovsky, Peter / Oko, Richard

    Biology of reproduction

    2019  Volume 101, Issue 2, Page(s) 368–376

    Abstract: The postacrosomal sheath (PAS) of the perinuclear theca (PT) is the first compartment of the sperm head to solubilize into the ooplasm upon sperm-oocyte fusion, implicating its constituents in zygotic development. This study investigates the role of one ... ...

    Abstract The postacrosomal sheath (PAS) of the perinuclear theca (PT) is the first compartment of the sperm head to solubilize into the ooplasm upon sperm-oocyte fusion, implicating its constituents in zygotic development. This study investigates the role of one such constituent, glutathione-S-transferase omega 2 (GSTO2), an oxidative-reductive enzyme found in the PAS and perforatorial regions of the PT. GSTO2 uses the conjugation of reduced glutathione, an electron donor shown to be compulsory in sperm disassembly within the ooplasm. The proximity of GSTO2 to the condensed sperm nucleus led us to hypothesize that this enzyme may facilitate nuclear decondensation by reducing disulfide bonds before the recruitment of GSTO enzymes from within the ooplasm. To test this hypothesis, we utilized a cell permeable isozyme-specific inhibitor, which fluoresces when bound to the active site of GSTO2, to functionally inhibit spermatozoa before performing intracytoplasmic sperm injections (ICSI) in mice. The technique allowed for targeted inhibition of solely PT-residing GSTO2, as all that is required for complete zygotic development is the injection of the mouse spermatozoon head. ICSI showed that inhibition of PT-anchored GSTO2 caused a delay in sperm nuclear decondensation, and further resulted in untimely embryo cleavage, and an increase in fragmentation beginning at the morula stage. The confounding effects of these developmental delays ultimately resulted in decreased blastocyst formation. This study implicates PT-anchored GSTO2 as an important facilitator of nuclear decondensation and reinforces the notion that the PAS-PT is a critical sperm compartment harboring molecules that facilitate zygotic development.
    MeSH term(s) Amino Acid Sequence ; Animals ; Female ; Glutathione Transferase/chemistry ; Glutathione Transferase/genetics ; Glutathione Transferase/metabolism ; Male ; Mice ; Sperm Head/physiology ; Sperm Injections, Intracytoplasmic/methods ; Sperm-Ovum Interactions/physiology ; Spermatozoa/enzymology
    Chemical Substances Glutathione Transferase (EC 2.5.1.18) ; Gsto2 protein, mouse (EC 2.5.1.18)
    Language English
    Publishing date 2019-05-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1118-6
    ISSN 1529-7268 ; 0006-3363
    ISSN (online) 1529-7268
    ISSN 0006-3363
    DOI 10.1093/biolre/ioz082
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  7. Article ; Online: The Orphan Nuclear Receptor Liver Homolog Receptor-1 (Nr5a2) Regulates Ovarian Granulosa Cell Proliferation.

    Meinsohn, Marie-Charlotte / Morin, Fanny / Bertolin, Kalyne / Duggavathi, Raj / Schoonjans, Kristina / Murphy, Bruce D

    Journal of the Endocrine Society

    2017  Volume 2, Issue 1, Page(s) 24–41

    Abstract: In mouse ovaries, liver receptor homolog-1 [nuclear receptor subfamily 5, group A, member 2 (Nr5a2)] expression is restricted to granulosa cells. Mice with Nr5a2 depletion in this cell population fail to ovulate. To determine whether Nr5a2 is essential ... ...

    Abstract In mouse ovaries, liver receptor homolog-1 [nuclear receptor subfamily 5, group A, member 2 (Nr5a2)] expression is restricted to granulosa cells. Mice with Nr5a2 depletion in this cell population fail to ovulate. To determine whether Nr5a2 is essential for granulosa cell proliferation during follicular maturation, we generated granulosa-specific conditional knockout mice (genotype Nr5a2 floxed Cre-recombinase driven by the anti-Müllerian type II receptor, hereafter cKO) with Nr5a2 depletion from primary follicles forward. Proliferation in cKO granulosa cells was substantially reduced relative to control (CON) counterparts, as assessed by bromodeoxyuridine incorporation, proliferative cell nuclear antigen expression, and fluorescent-activated cell sorting. Microarray analysis revealed >2000 differentially regulated transcripts between cKO and CON granulosa cells. Major gene ontology pathways disrupted were proliferation, steroid biosynthesis, female gamete formation, and ovulatory cycle. Transcripts for key cell-cycle genes, including
    Language English
    Publishing date 2017-12-01
    Publishing country United States
    Document type Journal Article
    ISSN 2472-1972
    ISSN (online) 2472-1972
    DOI 10.1210/js.2017-00329
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  8. Article ; Online: Durable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene.

    Vansandt, Lindsey M / Meinsohn, Marie-Charlotte / Godin, Philippe / Nagykery, Nicholas / Sicher, Natalie / Kano, Motohiro / Kashiwagi, Aki / Chauvin, Maeva / Saatcioglu, Hatice D / Barnes, Julie L / Miller, Amy G / Thompson, Amy K / Bateman, Helen L / Donelan, Elizabeth M / González, Raquel / Newsom, Jackie / Gao, Guangping / Donahoe, Patricia K / Wang, Dan /
    Swanson, William F / Pépin, David

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 3140

    Abstract: Eighty percent of the estimated 600 million domestic cats in the world are free-roaming. These cats typically experience suboptimal welfare and inflict high levels of predation on wildlife. Additionally, euthanasia of healthy animals in overpopulated ... ...

    Abstract Eighty percent of the estimated 600 million domestic cats in the world are free-roaming. These cats typically experience suboptimal welfare and inflict high levels of predation on wildlife. Additionally, euthanasia of healthy animals in overpopulated shelters raises ethical considerations. While surgical sterilization is the mainstay of pet population control, there is a need for efficient, safe, and cost-effective permanent contraception alternatives. Herein, we report evidence that a single intramuscular treatment with an adeno-associated viral vector delivering an anti-Müllerian hormone transgene produces long-term contraception in the domestic cat. Treated females are followed for over two years, during which transgene expression, anti-transgene antibodies, and reproductive hormones are monitored. Mating behavior and reproductive success are measured during two mating studies. Here we show that ectopic expression of anti-Müllerian hormone does not impair sex steroids nor estrous cycling, but prevents breeding-induced ovulation, resulting in safe and durable contraception in the female domestic cat.
    MeSH term(s) Cats ; Animals ; Female ; Anti-Mullerian Hormone/genetics ; Contraception/methods ; Contraception/veterinary ; Sterilization, Reproductive/methods ; Sterilization, Reproductive/veterinary ; Population Control/methods ; Animals, Wild ; Peptide Hormones
    Chemical Substances Anti-Mullerian Hormone (80497-65-0) ; Peptide Hormones
    Language English
    Publishing date 2023-06-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-38721-0
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  9. Article ; Online: WBP2 shares a common location in mouse spermatozoa with WBP2NL/PAWP and like its descendent is a candidate mouse oocyte-activating factor.

    Hamilton, Lauren E / Suzuki, Joao / Acteau, Genevieve / Shi, Mengqi / Xu, Wei / Meinsohn, Marie-Charlotte / Sutovsky, Peter / Oko, Richard

    Biology of reproduction

    2018  Volume 99, Issue 6, Page(s) 1171–1183

    Abstract: The sperm-borne oocyte-activating factor (SOAF) resides in the sperm perinuclear theca (PT). A consensus has been reached that SOAF most likely resides in the postacrosomal sheath (PAS), which is the first region of the PT to solubilize upon sperm-oocyte ...

    Abstract The sperm-borne oocyte-activating factor (SOAF) resides in the sperm perinuclear theca (PT). A consensus has been reached that SOAF most likely resides in the postacrosomal sheath (PAS), which is the first region of the PT to solubilize upon sperm-oocyte fusion. There are two SOAF candidates under consideration: PLCZ1 and WBP2NL. A mouse gene germline ablation of the latter showed that mice remain fertile with no observable phenotype despite the fact that a competitive inhibitor of WBP2NL, derived from its PPXY motif, blocks oocyte activation when coinjected with WBP2NL or spermatozoa. This suggested that the ortholog of WBP2NL, WBP2, containing the same domain and motifs associated with WBP2NL function, might compensate for its deficiency in oocyte activation. Our objectives were to examine whether WBP2 meets the developmental criteria established for SOAF and whether it has oocyte-activating potential. Immunoblotting detected WBP2 in mice testis and sperm and immunofluorescence localized WBP2 to the PAS and perforatorium of the PT. Immunohistochemistry of the testes revealed that WBP2 reactivity was highest in round spermatids and immunofluorescence detected WBP2 in the cytoplasmic lobe of elongating spermatids and colocalized it with the microtubular manchette during PT assembly. Microinjection of the recombinant forms of WBP2 and WBP2NL into metaphase II mouse oocytes resulted in comparable rates of oocyte activation. This study shows that WBP2 shares a similar testicular developmental pattern and location with WBP2NL and a shared ability to activate the oocyte, supporting its consideration as a mouse SOAF component that can compensate for a WBP2NL.
    MeSH term(s) Animals ; Antibodies ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cattle ; Humans ; Male ; Mice ; Oocytes/physiology ; Protein Transport ; Seminal Plasma Proteins/genetics ; Seminal Plasma Proteins/metabolism ; Species Specificity
    Chemical Substances Antibodies ; Carrier Proteins ; PAWP protein, mouse ; Seminal Plasma Proteins ; Wbp2 protein, mouse
    Language English
    Publishing date 2018-06-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1118-6
    ISSN 1529-7268 ; 0006-3363
    ISSN (online) 1529-7268
    ISSN 0006-3363
    DOI 10.1093/biolre/ioy156
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  10. Article ; Online: Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries.

    Meinsohn, Marie-Charlotte / Saatcioglu, Hatice D / Wei, Lina / Li, Yi / Horn, Heiko / Chauvin, Maeva / Kano, Motohiro / Nguyen, Ngoc Minh Phuong / Nagykery, Nicholas / Kashiwagi, Aki / Samore, Wesley R / Wang, Dan / Oliva, Esther / Gao, Guangping / Morris, Mary E / Donahoe, Patricia K / Pépin, David

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 20

    Abstract: Müllerian inhibiting substance (MIS/AMH), produced by granulosa cells of growing follicles, is an important regulator of folliculogenesis and follicle development. Treatment with exogenous MIS in mice suppresses follicle development and prevents ... ...

    Abstract Müllerian inhibiting substance (MIS/AMH), produced by granulosa cells of growing follicles, is an important regulator of folliculogenesis and follicle development. Treatment with exogenous MIS in mice suppresses follicle development and prevents ovulation. To investigate the mechanisms by which MIS inhibits follicle development, we performed single-cell RNA sequencing of whole neonatal ovaries treated with MIS at birth and analyzed at postnatal day 6, coinciding with the first wave of follicle growth. We identified distinct transcriptional signatures associated with MIS responses in the ovarian cell types. MIS treatment inhibited proliferation in granulosa, surface epithelial, and stromal cell types of the ovary and elicited a unique signature of quiescence in granulosa cells. In addition to decreasing the number of growing preantral follicles, we found that MIS treatment uncoupled the maturation of germ cells and granulosa cells. In conclusion, MIS suppressed neonatal follicle development by inhibiting proliferation, imposing a quiescent cell state, and preventing granulosa cell differentiation.
    MeSH term(s) Animals ; Animals, Newborn ; Anti-Mullerian Hormone/pharmacology ; Cell Differentiation/drug effects ; Female ; Inhibins/analysis ; Mice ; Mice, Inbred C57BL ; Ovarian Follicle/drug effects ; Ovarian Follicle/physiology ; Ovary/drug effects ; Ovary/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Peptide/analysis ; Receptors, Transforming Growth Factor beta/analysis ; Sequence Analysis, RNA ; Single-Cell Analysis ; Transcription, Genetic/drug effects
    Chemical Substances Receptors, Peptide ; Receptors, Transforming Growth Factor beta ; anti-Mullerian hormone receptor ; inhibin-alpha subunit ; Inhibins (57285-09-3) ; Anti-Mullerian Hormone (80497-65-0)
    Language English
    Publishing date 2021-05-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2100920118
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