{"doi":"10.1242/dev.204939","title":"In preprints: rethinking the foundations of the ovarian reserve","abstract":"For decades, the prevailing view of ovarian reserve formation – the process that provides the full complement of oocytes a female will carry for life – has been rooted in a mouse-centric model: a lineage-driven, binary process in which granulosa cells of distinct origins direct the fate of primordial follicles. However, a recent study by Wamaitha et al. challenges this longstanding view (Wamaitha et al., 2025 preprint). Using the rhesus macaque, a primate model that more closely aligns with human development, the authors present compelling evidence for a spatially governed mechanism in which location, rather than lineage, determines whether a follicle enters long-term dormancy or becomes prematurely activated. This departure from a lineage-based model to one governed by spatial factors challenges fundamental assumptions in developmental reproductive biology and paves the way for new insights into the origins of reproductive disorders such as primary ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS).During oogenesis, as oocytes transition from clusters of germ cells into individually encapsulated units, pre-granulosa (PG) cells surround each oocyte. This initiates the assembly of primordial follicles, the most immature stage of the follicular hierarchy (Wallace and Kelsey, 2010). Interactions between PGs and oocytes are crucial for follicle assembly, survival, and long-term dormancy. In the widely accepted ‘two-wave model’ based on mouse studies, two distinct PG lineages specify follicle fate (Niu and Spradling, 2020). The first wave governs the formation of short-lived follicles in the medullary region of the ovary that are activated early after birth. The second wave guides the formation of dormant, long-lived primordial follicles in the cortical region of the ovary, which constitute the ovarian reserve. This model proposes that granulosa cell lineage dictates follicle fate, determining whether a follicle remains quiescent or becomes activated. Although this model is appropriate for mice, primate developmental timelines, physiology and reproductive needs differ significantly (Cunha et al., 2019). The question of whether oogenesis aligns with this paradigm in humans and other primates remains unresolved.To address this conceptual gap, Wamaitha et al. combined single-cell RNA-sequencing, spatial transcriptomics and immunofluorescence microscopy of fetal ovaries obtained at different gestational stages (5 weeks post-conception to 6 months postnatal) from rhesus macaques, a species with a developmental timeline and ovarian architecture comparable to humans (Wagenen and Simpson, 1965). Across these stages, they identified three distinct PG cell populations: the expected PG1 and PG2 subtypes corresponding to the two-wave model in mice, and a novel PG1.5 population with intermediate transcriptional features. The authors found that all three granulosa subtypes contributed to quiescent and activated follicles, suggesting a developmental continuum rather than a strict binary lineage as in mice. Instead of lineage, the location of a follicle within the ovary was shown to determine its fate: quiescent follicles were restricted to the ovarian cortex, while activated follicles localized to the medulla region. Consistently, both dormant and activated follicles contain PG1.5 and PG2 cell types, confirming that granulosa identity alone does not dictate follicle fate in primates. This finding shifts the paradigm to the ovarian cortex as a regulator of follicular dormancy and identifies the medullary region as a trigger for follicle activation, a conceptual advance with significant implications for primate development.Alongside their redefinition of follicle fate, Wamaitha et al. uncovered a transient population of hormonally active medullary follicles that are activated by gestational week 19. They expressed CYP19A1 (aromatase) in estrogen-producing granulosa cells and CYP17A1 in androgen-producing theca-like cells – features of","journal":"Development","year":2025,"id":568596,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9421,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1266090,"name":"Binyam Mogessie","orcid":"0000-0002-0702-6356","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40518981","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}