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Kitl/kit signaling pathway regulate meiosis in mouse female gonad

ABSTRACT: The initiation of meiotic division, proper homologous chromosome pairing, and recombination are essential for maintaining genome stability in gametes. Numerous genes are involved in regulating these key processes during meiosis. However, the role of gonad somatic cells in regulating the initiation and progression of germ cell meiosis remains poorly understood. In this study, we identify the Kitl/Kit signaling pathway as a critical regulator of meiotic in female gonads. Disruption of Kitl/Kit signaling, both in vivo and in vitro, impairs the initiation of meiosis and leads to abnormalities in meiotic progression. We also observed that the mTOR/S6 signaling pathway is inhibited when Kitl/Kit signaling is blocked. Notably, adding a mTOR activator to in vitro cultures of Kitl conditional knockout gonads partially rescued germ cell numbers and improved meiotic initiation efficiency. Our findings highlight the essential role of the Kitl-Kit-mTOR-S6 signaling axis in meiotic initiation and progression. This study reveals a novel function of Kitl/Kit signaling in regulating embryonic meiosis and provides a new framework for future research on how somatic cells influence germ cell meiosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE283280 | GEO | 2026/02/20

REPOSITORIES: GEO

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Project description:Meiosis is a specialized form of cell division essential for sexual reproduction. The unique cellular events of meiosis have been extensively studied in model eukaryotes, including mammals. In mammals, the molecular and cellular changes that germ cells must undergo to transition from mitotic spermatogonia to meiotic spermatocytes remain largely undefined. Retinoic acid (RA) has been proposed as the meiosis inducing substance (MIS) required for female and male meiotic initiation. However, evidence for this presumption is based on studies of fetal gonads – meiosis is initiated in fetal ovaries but suppressed in fetal testes. Critically, the requirement for RA in meiosis has never been formally tested because germ cell differentiation and meiotic initiation in the fetal ovary are temporally inseparable. Using the postnatal mouse testis, where differentiation and meiotic initiation are temporally distinct (8.6 days apart), we test the hypothesis that RA is dispensable for initiation and progression through meiosis. Complementary in vivo experimental models were designed to address the hypothesis. In the first, “RA-sufficient” (RA-suf) model, spermatogenesis was synchronized by administration of potent and selective RA synthesis inhibitor; as a result, testes contained only undifferentiated spermatogonia. Then, the inhibitor was discontinued, and mice were given a single dose of exogenous RA to initiate spermatogonial differentiation. Germ cells completed differentiation, entered and completed meiosis, and formed haploid gametes at predicted timepoints. In the second, “RA-deficient” (RA-def) model, mice were treated as above, except the inhibitor was administered continuously. The lack of testicular RA in this model was confirmed in multiple ways, including assessment of RA-responsive gene expression, in vitro serum-free cultures, and dose-response experiments. To our surprise, germ cells in RA-def testes completed differentiation, underwent meiotic DNA replication, completed the landmark cytological processes of meiosis, and formed postmeiotic haploid spermatids, all on the predicted timeline of the RA-suf model. To define the effect of RA-deficiency on gene expression during meiotic initiation, large, highly enriched populations of premeiotic spermatogonia from RA-suf mice, and meiotic preleptotene spermatocytes from both models were FACS-isolated and subjected to bulk RNA-seq. Interestingly, analyses revealed few significant differences in expression of characteristic meiotic genes at the mRNA level. However, genes that were significantly different between RA-suf and RA-def preleptotene spermatocytes were associated with spermiogenesis functions. Taken together, our data reveal that, after initiating spermatogonial differentiation, RA is dispensable for initiation, progression through, and completion of meiosis in the male germline.

Project description:Ray2013 - Meiotic initiation in S. cerevisiae A mathematical representation of early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signalling molecules for regulating protein activities, is described here This model is described in the article: Dynamic modeling of yeast meiotic initiation. Ray D, Su Y, Ye P. BMC Syst Biol. 2013 May 1;7:37 Abstract: BACKGROUND: Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities. RESULTS: The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state. CONCLUSIONS: By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity. This model is hosted on BioModels Database and identified by: BIOMD0000000626 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Kitl/kit signaling pathway regulate meiosis in mouse female gonad

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