Two Distinct Pathways of Pregranulosa Cell Differentiation Support Follicle Formation in the Mouse Ovary

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Aug 8

PMID 32759216

Citations 95

Authors

Wanbao Niu

Allan C Spradling

Affiliations

Soon will be listed here.

Abstract

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, bipotential pregranulosa (BPG) cells, derives directly from bipotential precursors, expresses Foxl2 early, and associates with cysts throughout the ovary by E12.5. A second PG group, epithelial pregranulosa (EPG) cells, arises in the ovarian surface epithelium, ingresses cortically by E12.5 or earlier, expresses Lgr5, but delays robust Foxl2 expression until after birth. By E19.5, EPG cells predominate in the cortex and differentiate into granulosa cells of quiescent primordial follicles. In contrast, medullar BPG cells differentiate along a distinct pathway to become wave 1 granulosa cells. Reflecting their separate somatic cellular lineages, second wave follicles were ablated by diptheria toxin treatment of Lgr5-DTR-EGFP mice at E16.5 while first wave follicles developed normally and supported fertility. These studies provide insights into ovarian somatic cells and a resource to study the development, physiology, and evolutionary conservation of mammalian ovarian follicles.

Citing Articles

Characterizing the Ovarian Cytogenetic Dynamics of Sichuan Bream () During Vitellogenesis at a Single-Cell Resolution.

Zhao Z, Huang S, Feng Q, Peng L, Zhao Q, Wang Z Int J Mol Sci. 2025; 26(5).

PMID: 40076886 PMC: 11900179. DOI: 10.3390/ijms26052265.

Defining the cell and molecular origins of the primate ovarian reserve.

Wamaitha S, Rojas E, Monticolo F, Hsu F, Sosa E, Mackie A bioRxiv. 2025; .

PMID: 39896577 PMC: 11785033. DOI: 10.1101/2025.01.21.634052.

The evolution of ovarian somatic cells characterized by transcriptome and chromatin accessibility across rodents, monkeys, and humans.

Zhang Q, Sun F, Zhang R, Zhao D, Zhu R, Cheng X Life Med. 2025; 3(5):lnae028.

PMID: 39872443 PMC: 11749874. DOI: 10.1093/lifemedi/lnae028.

The neonatal ketone body is important for primordial follicle pool formation and regulates ovarian ageing in mice.

Wang X, Zhang X, Sang Y, Chong D, Sheng X, Wang H Life Metab. 2025; 1(2):149-160.

PMID: 39872353 PMC: 11749118. DOI: 10.1093/lifemeta/loac017.

Single-cell RNA sequencing reveals the intercellular crosstalk and the regulatory landscape of stromal cells during the whole life of the mouse ovary.

Jiang W, Sun W, Peng Y, Xu H, Fan H, Jin X Life Med. 2025; 3(6):lnae041.

PMID: 39872151 PMC: 11748273. DOI: 10.1093/lifemedi/lnae041.

References

Ku C, Johnson P, Batten P, Sarathchandra P, Chambers R, Taylor P . Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res. 2006; 71(3):548-56. DOI: 10.1016/j.cardiores.2006.03.022. View

Jung M, Wells D, Rusch J, Ahmad S, Marchini J, Myers S . Unified single-cell analysis of testis gene regulation and pathology in five mouse strains. Elife. 2019; 8. PMC: 6615865. DOI: 10.7554/eLife.43966. View

McLaren A . Development of the mammalian gonad: the fate of the supporting cell lineage. Bioessays. 1991; 13(4):151-6. DOI: 10.1002/bies.950130402. View

Kai T, Spradling A . An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proc Natl Acad Sci U S A. 2003; 100(8):4633-8. PMC: 153607. DOI: 10.1073/pnas.0830856100. View

Minkina A, Matson C, Lindeman R, Ghyselinck N, Bardwell V, Zarkower D . DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev Cell. 2014; 29(5):511-520. PMC: 4105363. DOI: 10.1016/j.devcel.2014.04.017. View

Abby E, Tourpin S, Ribeiro J, Daniel K, Messiaen S, Moison D . Implementation of meiosis prophase I programme requires a conserved retinoid-independent stabilizer of meiotic transcripts. Nat Commun. 2016; 7:10324. PMC: 4729902. DOI: 10.1038/ncomms10324. View

Wang Y, Teng Z, Li G, Mu X, Wang Z, Feng L . Cyclic AMP in oocytes controls meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary. Development. 2014; 142(2):343-51. DOI: 10.1242/dev.112755. View

Myers M, Middlebrook B, Matzuk M, Pangas S . Loss of inhibin alpha uncouples oocyte-granulosa cell dynamics and disrupts postnatal folliculogenesis. Dev Biol. 2009; 334(2):458-67. PMC: 2753717. DOI: 10.1016/j.ydbio.2009.08.001. View

Anderson E, Baltus A, Roepers-Gajadien H, Hassold T, de Rooij D, van Pelt A . Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A. 2008; 105(39):14976-80. PMC: 2542382. DOI: 10.1073/pnas.0807297105. View

10.

Karl J, Capel B . Sertoli cells of the mouse testis originate from the coelomic epithelium. Dev Biol. 1998; 203(2):323-33. DOI: 10.1006/dbio.1998.9068. View

11.

Fujino A, Pieretti-Vanmarcke R, Wong A, Donahoe P, Arango N . Sexual dimorphism of G-protein subunit Gng13 expression in the cortical region of the developing mouse ovary. Dev Dyn. 2007; 236(7):1991-6. DOI: 10.1002/dvdy.21183. View

12.

Bagheri-Fam S, Chen H, Wilson S, Ayers K, Hughes J, Sloan-Bena F . The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice. PLoS One. 2020; 15(1):e0227411. PMC: 6946174. DOI: 10.1371/journal.pone.0227411. View

13.

Lei L, Spradling A . Mouse primordial germ cells produce cysts that partially fragment prior to meiosis. Development. 2013; 140(10):2075-81. PMC: 3640216. DOI: 10.1242/dev.093864. View

14.

Gao Y, Mao Y, Xu R, Zhu R, Zhang M, Sun J . Defining gene networks controlling the maintenance and function of the differentiation niche by an in vivo systematic RNAi screen. J Genet Genomics. 2019; 46(1):19-30. DOI: 10.1016/j.jgg.2018.10.008. View

15.

Nokelainen P, Peltoketo H, Vihko R, Vihko P . Expression cloning of a novel estrogenic mouse 17 beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase (m17HSD7), previously described as a prolactin receptor-associated protein (PRAP) in rat. Mol Endocrinol. 1998; 12(7):1048-59. DOI: 10.1210/mend.12.7.0134. View

16.

Lewis S, Erickson R, BARNETT L, Venta P, TASHIAN R . N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: an animal model for human carbonic anhydrase II deficiency syndrome. Proc Natl Acad Sci U S A. 1988; 85(6):1962-6. PMC: 279901. DOI: 10.1073/pnas.85.6.1962. View

17.

Wang X, Page-McCaw A . Wnt6 maintains anterior escort cells as an integral component of the germline stem cell niche. Development. 2018; 145(3). PMC: 5818006. DOI: 10.1242/dev.158527. View

18.

Lin Y, Gill M, Koubova J, Page D . Germ cell-intrinsic and -extrinsic factors govern meiotic initiation in mouse embryos. Science. 2008; 322(5908):1685-7. DOI: 10.1126/science.1166340. View

19.

Garcia-Ortiz J, Pelosi E, Omari S, Nedorezov T, Piao Y, Karmazin J . Foxl2 functions in sex determination and histogenesis throughout mouse ovary development. BMC Dev Biol. 2009; 9:36. PMC: 2711087. DOI: 10.1186/1471-213X-9-36. View

20.

Zhou J, Stein P, Leu N, Chmatal L, Xue J, Ma J . Accelerated reproductive aging in females lacking a novel centromere protein SYCP2L. Hum Mol Genet. 2015; 24(22):6505-14. PMC: 4614708. DOI: 10.1093/hmg/ddv359. View