Review

Authors: Jingyi Gao, Yiwen Qin, John C Schimenti...

Meiosis is essential for gamete production in all sexually reproducing organisms. It entails two successive cell divisions without DNA replication, producing haploid cells from diploid ones. This process involves complex morphological and molecular differentiation that varies across species and between sexes. Specialized genomic events like meiotic recombination and chromosome segregation are tightly regulated, including preparation for post-meiotic development. Research in model organisms, notably yeast, has shed light on the genetic and molecular aspects of meiosis and its regulation. Although mammalian meiosis research faces challenges, particularly in replicating gametogenesis in vitro, advances in genetic and genomic technologies are providing mechanistic insights. Here we review the genetics and molecular biology of meiotic gene expression control, focusing on mammals.

Topics: Animals; Meiosis; Saccharomyces cerevisiae; Gametogenesis; Chromosome Segregation; DNA Replication; Mammals

PubMed: 38177041
DOI: 10.1016/j.tig.2023.12.006

Review

Authors: Hailey Larose, Adrienne Niederriter Shami, Haley Abbott...

Gametogenesis, the process of forming mature germ cells, is an integral part of both an individual's and a species' health and well-being. This chapter focuses on critical male and female genetic and epigenetic processes underlying normal gamete formation through their differentiation to fertilization. Finally, we explore how knowledge gained from this field has contributed to progress in areas with great clinical promise, such as in vitro gametogenesis.

Topics: Animals; Cell Differentiation; Embryonic Stem Cells; Female; Fertilization; Gametogenesis; Gene Expression Regulation, Developmental; Germ Cells; Humans; Male

PubMed: 30797511
DOI: 10.1016/bs.ctdb.2018.12.006

Authors: Yao Chen, Yuxuan Zheng, Yun Gao...

A systematic interrogation of male germ cells is key to complete understanding of molecular mechanisms governing spermatogenesis and the development of new strategies for infertility therapies and male contraception. Here we develop an approach to purify all types of homogeneous spermatogenic cells by combining transgenic labeling and synchronization of the cycle of the seminiferous epithelium, and subsequent single-cell RNA-sequencing. We reveal extensive and previously uncharacterized dynamic processes and molecular signatures in gene expression, as well as specific patterns of alternative splicing, and novel regulators for specific stages of male germ cell development. Our transcriptomics analyses led us to discover discriminative markers for isolating round spermatids at specific stages, and different embryo developmental potentials between early and late stage spermatids, providing evidence that maturation of round spermatids impacts on embryo development. This work provides valuable insights into mammalian spermatogenesis, and a comprehensive resource for future studies towards the complete elucidation of gametogenesis.

Topics: Animals; Male; Mice; Mice, Inbred Strains; Sequence Analysis, RNA; Single-Cell Analysis; Spermatogenesis

PubMed: 30061742
DOI: 10.1038/s41422-018-0074-y

Review

Authors: Ronit Machtinger, Louise C Laurent, Andrea A Baccarelli...

BACKGROUND

Extracellular vesicles (EVs) are membrane-bound vesicles, found in biofluids, that carry and transfer regulatory molecules, such as microRNAs (miRNAs) and proteins, and may mediate intercellular communication between cells and tissues. EVs have been isolated from a wide variety of biofluids, including plasma, urine, and, relevant to this review, seminal, follicular and uterine luminal fluid. We conducted a systematic search of the literature to review and present the currently available evidence on the possible roles of EVs in follicular growth, resumption of oocyte development and maturation (meiosis), sperm maturation, fertilization and embryo implantation.

METHODS

MEDLINE, Embase and Web of Science databases were searched using keywords pertaining to EVs, including 'extracellular vesicles', 'microvesicles', 'microparticles' and 'exosomes', combined with a range of terms associated with the period of development between fertilization and implantation, including 'oocyte', 'sperm', 'semen', 'fertilization', 'implantation', 'embryo', 'follicular fluid', 'epididymal fluid' and 'seminal fluid'. Relevant research articles published in English (both animal and human studies) were reviewed with no restrictions on publication date (i.e. from earliest database dates to July 2015). References from these articles were used to obtain additional articles.

RESULTS

A total of 1556 records were retrieved from the three databases. After removing duplicates and irrelevant titles, we reviewed the abstracts of 201 articles, which included 92 relevant articles. Both animal and human studies unequivocally identified various types of EVs in seminal, follicular and ULFs. Several studies provided evidence for the roles of EVs in these biofluids. In men, EVs in seminal fluid were linked with post-testicular sperm maturation, including sperm motility acquisition and reduction of oxidative stress. In women, EVs in follicular fluid were shown to contain miRNAs with potential roles in follicular growth, resumption of oocyte meiosis, steroidogenesis and prevention of polyspermy after fertilization. EVs were also detected in the media of cultured embryos, suggesting that EVs released from embryos and the uterus may mediate embryo-endometrium cross-talk during implantation. It is important to note that many of the biologically plausible functions of EVs in reproduction discussed in the current literature have not yet been substantiated by conclusive experimental evidence.

CONCLUSIONS

A detailed understanding of the contributions of EVs in the series of events from gametogenesis to fertilization and then on to implantation, in both normal and pathological cases, may enable the development of valuable tools to advance reproductive health. Because of the early stage of the field, it is unsurprising that the current literature includes not only growing experimental evidence, but also as-yet unproven hypotheses pertaining to the roles of EVs in key reproductive processes. In this review, we present a comprehensive survey of the rapidly expanding literature on this subject, highlighting both relevant findings and gaps in knowledge.

Topics: Animals; Cell Communication; Embryo Implantation; Extracellular Vesicles; Female; Fertilization; Humans; Male; Oocytes; Oogenesis; Pregnancy; Semen; Spermatogenesis

PubMed: 26663221
DOI: 10.1093/humupd/dmv055

Review

Authors: Julie A Law, Steven E Jacobsen

Cytosine DNA methylation is a stable epigenetic mark that is crucial for diverse biological processes, including gene and transposon silencing, imprinting and X chromosome inactivation. Recent findings in plants and animals have greatly increased our understanding of the pathways used to accurately target, maintain and modify patterns of DNA methylation and have revealed unanticipated mechanistic similarities between these organisms. Key roles have emerged for small RNAs, proteins with domains that bind methylated DNA and DNA glycosylases in these processes. Drawing on insights from both plants and animals should deepen our understanding of the regulation and biological significance of DNA methylation.

Topics: Animals; CpG Islands; DNA Methylation; DNA, Plant; Epigenesis, Genetic; Gametogenesis; Histones; Models, Genetic; Plants; RNA, Small Interfering

PubMed: 20142834
DOI: 10.1038/nrg2719

Authors: Jingtao Guo, Xichen Nie, Maria Giebler...

The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.

Topics: Adult; Humans; Infant; Male; Puberty; Sertoli Cells; Spermatogenesis; Spermatogonia; Testis

PubMed: 31928944
DOI: 10.1016/j.stem.2019.12.005

Authors: Yukiko Ishikura, Hiroshi Ohta, Takuya Sato...

Mammalian male germ-cell development consists of three distinct phases: primordial germ cell (PGC) development, male germ-cell specification for spermatogonium development, and ensuing spermatogenesis. Here, we show an in vitro reconstitution of whole male germ-cell development by pluripotent stem cells (PSCs). Mouse embryonic stem cells (mESCs) are induced into PGC-like cells (mPGCLCs), which are expanded for epigenetic reprogramming. In reconstituted testes under an optimized condition, such mPGCLCs differentiate into spermatogonium-like cells with proper developmental transitions, gene expression, and cell-cycle dynamics and are expanded robustly as germline stem cell-like cells (GSCLCs) with an appropriate androgenetic epigenome. Importantly, GSCLCs show vigorous spermatogenesis, not only upon transplantation into testes in vivo but also under an in vitro culture of testis transplants, and the resultant spermatids contribute to fertile offspring. By uniting faithful recapitulations of the three phases of male germ-cell development, our study creates a paradigm for the in vitro male gametogenesis by PSCs.

Topics: Animals; Cell Differentiation; Epigenomics; Germ Cells; Male; Mice; Pluripotent Stem Cells; Spermatogenesis; Spermatogonia

PubMed: 34496297
DOI: 10.1016/j.stem.2021.08.005

Authors: Yue Lv, Gang Lu, Yuling Cai...

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.

Topics: Animals; Mice; 3' Untranslated Regions; Cell Cycle Proteins; Gametogenesis; Meiosis; Nuclear Proteins; RNA-Binding Proteins; Cohesins

PubMed: 36726756
DOI: 10.1093/procel/pwac040

Review

Authors: James A MacLean, Miles F Wilkinson

Homeobox genes encode transcription factors that have crucial roles in embryogenesis. A recently discovered set of homeobox genes--the Rhox genes--are expressed during both embryogenesis and in adult reproductive tissues. The 33 known mouse Rhox genes are clustered together in a single region on the X chromosome, while likely descendents of the primodial Rhox cluster, Arx and Esx1, have moved to other positions on the X chromosome. Here, we summarize what is known about the regulation and function of Rhox cluster and Rhox-related genes during embryogenesis and gametogenesis. The founding member of the Rhox gene cluster--Rhox5 (previously known as Pem)--has been studied in the most depth and thus is the focus of this review. We also discuss the unusually rapid evolution of the Rhox gene cluster.

Topics: Animals; Embryonic Development; Female; Gametogenesis; Gene Expression Regulation; Genes, Homeobox; Mice; Multigene Family; Pregnancy; Transcription Factors

PubMed: 20430877
DOI: 10.1530/REP-10-0100

Authors: Allan C Spradling, Wanbao Niu, Qi Yin...

Recent studies show that pre-follicular mouse oogenesis takes place in germline cysts, highly conserved groups of oogonial cells connected by intercellular bridges that develop as nurse cells as well as an oocyte. Long studied in and insect gametogenesis, female germline cysts acquire cytoskeletal polarity and traffic centrosomes and organelles between nurse cells and the oocyte to form the Balbiani body, a conserved marker of polarity. Mouse oocyte development and nurse cell dumping are supported by dynamic, cell-specific programs of germline gene expression. High levels of perinatal germ cell death in this species primarily result from programmed nurse cell turnover after transfer rather than defective oocyte production. The striking evolutionary conservation of early oogenesis mechanisms between distant animal groups strongly suggests that gametogenesis and early embryonic development in vertebrates and invertebrates share even more in common than currently believed.

Topics: Female; Pregnancy; Mice; Animals; Drosophila; Oogenesis; Germ Cells; Oocytes; Gametogenesis

PubMed: 36445738
DOI: 10.7554/eLife.83230