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Challenging the role of retinoic acid in meiotic initiation

挑战视黄酸在减数分裂起始中的作用

基本信息

批准号：
10453019
负责人：
Christopher Bennett Geyer
金额：
$ 23.27万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453019
关键词：
Animal Model Attention Blood-Testis Barrier Collaborations Contraceptive Agents Cytology DNA DNA biosynthesis Data Development Drug Delivery Systems Drug Targeting Environment Enzymes Eukaryota Event Fertility Fluorescence Foundations Funding Mechanisms Future Gene Expression Gene Expression Regulation Genes Germ Cells Haploidy Health Human Male Contraceptive Agents Mammals Mass Spectrum Analysis Mediating Meiosis Meiotic Prophase I Meiotic Recombination Messenger RNA Mitotic Molecular Mus Outcome Phase Physiologic pulse Polyribosomes Population Post-Transcriptional Regulation Proteins Proteome Proteomics RNA Receptor Signaling Resources Ribosomes Role Sexual Reproduction Shotguns Signal Pathway Signaling Molecule Sister Chromatid Spermatids Spermatocytes Spermatogenesis Spermatogonia Surveys Testing Testis Transgenic Mice Translating Tretinoin Work Yeasts base cell type cohesion contraceptive target design drug development experimental study follow-up gene product homologous recombination in vivo male male fertility mouse model novel postnatal programs segregation sex small molecule inhibitor stem cells transcriptome translatome

项目摘要

PROJECT SUMMARY/ABSTRACT Meiosis is essential for sexual reproduction, and its specialized molecular and cellular programs have been intensely studied in lower eukaryotes and mammals. In mammals, however, the transition from mitotic spermatogonia into the meiotic program, termed meiotic initiation, has received little attention. Meiotic initiation occurs during the preleptotene phase of meiotic prophase I, as these spermatocytes replicate their DNA and prepare for meiotic recombination and segregation. Retinoic acid (RA) has been proposed to serve as the ‘meiosis inducing substance.’ In the postnatal testis, although it is clearly required for spermatogonial differentiation, our exciting preliminary data reveals RA is dispensable 8.6 days later for meiotic initiation. Thus, the role of RA in meiosis has not been properly examined, and the true meiosis- inducing factor(s) remain undefined. This proposal represents a new collaboration between the Geyer and Schindler labs, who will work together to uncover the true role(s) for RA in meiosis. In Aim 1, we will identify the specific requirement for RA in initiation and progression through meiosis to form haploid spermatids. In Aim 2, we will employ a novel transgenic mouse model with synchronized spermatogenesis for fluorescence-based isolation of millions of germ cells prior to and during meiotic initiation. Using this unique resource, we will define and compare RA-mediated changes in gene expression at the transcriptome (RNA abundance), translatome (translating RNAs), and proteome (protein abundance) levels during meiotic initiation. The outcome of this work is identification of novel regulators of this critical transition, and testis-specific proteins that are upregulated in preleptotene spermatocytes will represent putative male contraceptive targets. Indeed, preleptotene spermatocytes represent an ideal cell type for male contraceptive drug development, for two reasons: 1) they reside outside the blood-testis-barrier (BTB), which is a significant barrier to drug delivery; and 2) they are distinct from the spermatogonial stem cell (SSC) pool, and thus can be targeted without irreversibly damaging the male germline. The results from this proposal will be foundational to defining the broader mechanistic relationship between RA and meiosis that are essential for male fertility.

项目总结/文摘