Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries

Published on May 18, 2021in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.2100920118
Marie-Charlotte Meinsohn8
Estimated H-index: 8
(Harvard University),
Hatice D. Saatcioglu7
Estimated H-index: 7
(Harvard University)
+ 14 AuthorsDavid Pépin15
Estimated H-index: 15
(Harvard University)
Mullerian 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.
#1Marie-Charlotte Meinsohn (UdeM: Université de Montréal)H-Index: 8
#2Camilla H K Hughes (UdeM: Université de Montréal)H-Index: 1
Last. Bruce D. Murphy (UdeM: Université de Montréal)H-Index: 43
view all 7 authors...
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 f...
1 CitationsSource
#1Loes M.E. Moolhuijsen (EUR: Erasmus University Rotterdam)H-Index: 1
#2Jenny A. Visser (EUR: Erasmus University Rotterdam)H-Index: 51
CONTEXT Anti-Mullerian hormone is produced by granulosa cells of small growing follicles in the ovary. Serum AMH levels strongly correlate with the number of growing follicles, and therefore it has received increasing attention as a marker for ovarian reserve. This review summarizes recent findings and limitations in the application of serum AMH in ovarian reserve assessment. EVIDENCE ACQUISITION A PubMed search was conducted to find recent literature on the measurements and use of serum AMH as ...
6 CitationsSource
#1Yao ChenH-Index: 1
#2Weina YangH-Index: 2
Last. Donghui Huang (HUST: Huazhong University of Science and Technology)H-Index: 1
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Mammalian ovaries consist of follicles as basic functional units. Each follicle comprised an innermost oocyte and several surrounding flattened granulosa cells. Unlike males, according to the initial size of the primordial follicle pool and the rate of its activation and depletion, a female's reproductive life has been determined early in life. Primordial follicles, once activated, will get into an irreversible process of development. Most follicles undergo atretic degeneration, and only a few o...
#1Hadrian M Kinnear (UM: University of Michigan)H-Index: 4
#2Claire E Tomaszewski (UM: University of Michigan)H-Index: 3
Last. Ariella Shikanov (UM: University of Michigan)H-Index: 24
view all 7 authors...
Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune...
3 CitationsSource
#1Wanbao Niu (CIS: Carnegie Institution for Science)H-Index: 1
#2Allan C. Spradling (CIS: Carnegie Institution for Science)H-Index: 90
We sequenced more than 52,500 single cells from embryonic day 11.5 (E11.5) postembryonic day 5 (P5) gonads and performed lineage tracing to analyze primordial follicles and wave 1 medullar follicles during mouse fetal and perinatal oogenesis. Germ cells clustered into six meiotic substages, as well as dying/nurse cells. Wnt-expressing bipotential precursors already present at E11.5 are followed at each developmental stage by two groups of ovarian pregranulosa (PG) cells. One PG group, bipotentia...
20 CitationsSource
#1Qiyu Yang (HUST: Huazhong University of Science and Technology)H-Index: 2
#2Lixia Zhu (HUST: Huazhong University of Science and Technology)H-Index: 1
Last. Lei Jin (HUST: Huazhong University of Science and Technology)H-Index: 11
view all 3 authors...
Fertility preservation has received unprecedented attention nowadays. In addition to cryopreservation and re-implantation of embryos, oocytes, and ovarian tissue pieces, in vitro culture system for follicles and oocytes has been considered as an alternative strategy for fertility preservation. Since the metabolic dynamics and required nutrients are not entirely the same in different stages of follicular development, optimization of each culture step is needed. In this paper, literature regarding...
2 CitationsSource
#1Ruikang Guo (University of Otago)H-Index: 1
#2Michael W. Pankhurst (University of Otago)H-Index: 13
Anti-Mullerian hormone (AMH) inhibits the activation of primordial follicles in the ovary. This causes an increased rate of ovarian reserve depletion in Amh-/- mice. The depletion of the ovarian reserve is responsible for the onset of menopause but age-related infertility occurs in advance of ovarian reserve depletion. To determine whether accelerated loss of primordial follicles leads to earlier onset infertility, Amh-/- and Amh+/+ females were paired with Amh+/+ stud males and birth rates were...
#1Marla E. Tharp (Johns Hopkins University)H-Index: 2
#1Marla E. Tharp (CIS: Carnegie Institution for Science)H-Index: 1
Last. Alex Bortvin (CIS: Carnegie Institution for Science)H-Index: 17
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Female reproductive success critically depends on the size and quality of a finite ovarian reserve. Paradoxically, mammals eliminate up to 80% of the initial oocyte pool through the enigmatic process of fetal oocyte attrition (FOA). Here, we interrogate the striking correlation of FOA with retrotransposon LINE-1 (L1) expression in mice to understand how L1 activity influences FOA and its biological relevance. We report that L1 activity triggers FOA through DNA damage-driven apoptosis and the com...
10 CitationsSource
#1Motohiro Kano (Harvard University)H-Index: 2
#2J.Y. Hsu (Harvard University)H-Index: 4
Last. David Pépin (Harvard University)H-Index: 15
view all 8 authors...
: Mullerian-inhibiting substance (MIS), also known as anti-Mullerian hormone, is thought to be a negative regulator of primordial follicle activation. We have previously reported that treatment with exogenous MIS can induce complete ovarian suppression within 5 weeks of treatment in mice. To investigate the kinetics of the return of folliculogenesis following the reversal of suppression, we treated animals with recombinant human MIS (rhMIS) protein for 40 days in adult female Nu/Nu mice and moni...
1 CitationsSource
#1Hatice D. Saatcioglu (Harvard University)H-Index: 7
#2Motohiro Kano (Harvard University)H-Index: 2
Last. David Pépin (Harvard University)H-Index: 15
view all 19 authors...
In the womb, mammals possess all of the preliminary sexual structures necessary to become either male or female. This includes the Mullerian duct, which develops into the Fallopian tubes, uterus, cervix, and vagina in female fetuses. In male fetuses, the testis secretes a hormone called Mullerian inhibiting substance (MIS). This triggers the activity of a small group of cells, known as Misr2+ cells, that cause the Mullerian duct to degenerate, preventing males from developing female sexual organ...
10 CitationsSource
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