Reproductive biology is closely associated with human health and social progress. Modern reproductive biology research in China began in the 1930s. Advances in science, technology, government support, and international collaborations spawned the rapid growth of reproductive biology research in China. While the development of reproductive biology has provided both theoretical knowledge and applicable technologies, it has also generated new social and ethical concerns. This review summarizes and highlights the contributions of modern reproductive biology research in China, with a specific focus on aspects that are most related to human reproduction and health.

Reproductive medicine in China has developed rapidly since 1988 due to support from the government and scientific exploration. However, the success rate of assisted reproduction technology is around 30–40% and many unknown “black boxes” in gametogenesis and embryo development are still present. With the development of single-cell and low-input sequencing technologies, the network of transcriptome and epigenetic regulation (DNA methylation, chromatin accessibility, and histone modifications) during the development of human primordial germ cells, gametes, and embryos has been investigated in depth. Furthermore, preimplantation genetic testing has also rapidly developed. In this review, we summarize and analyze China's outstanding progress in these fields.

Summary Sentence

An overview of development of human gametes and embryos, including the dynamic changes and its biological significance of transcriptome and epigenetic regulatory networks in human primordial germ cells, gametes, and early embryonic development.

Premature ovarian insufficiency (POI) is one of the key aspects of ovarian infertility. Due to early cession of ovarian function, POI imposes great challenges on the physiological and psychological health of women and becomes a common cause of female infertility. In the worldwide, there has been a special outpouring of concern for about 4 million reproductive-aged women suffering from POI in China. Driven by advances in new technologies and efforts invested by Chinses researchers, understanding about POI has constantly been progressing over the past decade. Here, we comprehensively summarize and review the landmark development and achievements from POI studies in China spanning 2011–2020, which aims to provide key insights from bench to bedside.

Summary Sentence

In this review, we offered a glimpse on POI research by Chinese researchers and highlighted leading developments and landmark achievements in etiological, diagnostic, and therapeutic progress in the past decade.

Innovations in ultrasensitive and single-cell measurements enable us to study layers of genome regulation in view of cellular and regulatory heterogeneity. Genome-scale mapping allows to evaluate epigenetic features and dynamics in different genomic contexts, including genebodies, CpG islands, imprinting control regions, promoters, partially methylated domains, and repetitive elements. The epigenome of early embryos, fetal germ cells, and sperms has been extensively studied for the past decade, whereas oocytes remain less clear. Emerging evidence now supports the notion that transcription and chromatin accessibility precede de novo DNA methylation in both human and mouse oocytes. Recent studies have also started to chart correlations among different histone modifications and DNA methylation. We discuss the potential mechanistic hierarchy that shapes the oocyte DNA methylome, also providing insights into the convergent and divergent features between humans and mice.

Summary Sentence

Both human and mouse oocytes represent unique epigenomic landscapes. De novo DNA methylation occurs in growing oocytes, which correlates with transcription and chromatin accessibility.

Graphical Abstract

Well balanced and timed metabolism is essential for oocyte development. The effects of extrinsic nutrients on oocyte maturation have been widely reported. In contrast, intrinsic control of oogenesis by intracellular metabolites and metabolic enzymes has received little attention. The comprehensive characterization of metabolic patterns could lead to more complete understanding of regulatory mechanisms underlying oocyte development. A cell's metabolic state is integrated with epigenetic regulation. Epigenetic modifications in germ cells are therefore sensitive to parental environmental exposures. Nevertheless, direct genetic evidence for metabolites involvement in epigenetic establishment during oocyte development is still lacking. Moreover, metabolic disorder-induced epigenetic perturbations during oogenesis might mediate the inter/transgenerational effects of environmental insults. The molecular mechanisms responsible for this deserve further investigation. Here, we summarize the findings on metabolic regulation in oocyte maturation, and how it contributes to oocyte epigenetic modification. Finally, we propose a mouse model that metabolic disorder in oocyte serves as a potential factor mediating the maternal environment effects on offspring health.

RNA—the primary product of the genome—is subject to various biological events during its lifetime. During mammalian gametogenesis and early embryogenesis, germ cells and preimplantation embryos undergo marked changes in the transcriptome, including mRNA turnover. Various factors, including specialized proteins, RNAs, and organelles, function in an intricate degradation system, and the degradation selectivity is determined by effectors and their target mRNAs. RNA homeostasis regulators and surveillance factors function in the global transcriptome of oocytes and somatic cells. Other factors, including BTG4, PABPN1L, the CCR4-NOT subunits, CNOT6L and CNOT7, and TUTs, are responsible for two maternal mRNA avalanches: M- and Z-decay. In this review, we discuss recent advances in mRNA degradation mechanisms in mammalian oocytes and preimplantation embryos. We focused on the studies in mice, as a model mammalian species, and on RNA turnover effectors and the cis-elements in targeting RNAs.

Coordinated development of the germline and the somatic compartments within a follicle is an essential prerequisite for creating a functionally normal oocyte. Bi-directional communication between the oocyte and the granulosa cells enables the frequent interchange of metabolites and signals that support the development and functions of both compartments. Mechanistic target of rapamycin (MTOR), a conserved serine/threonine kinase and a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation, is emerging as a major player that regulates many facets of oocyte and follicle development. Here, we summarized our recent observations on the role of oocyte- and granulosa cell-expressed MTOR in the control of the oocyte's and granulosa cell's own development, as well as the development of one another, and provided new data that further strengthen the role of cumulus cell-expressed MTOR in synchronizing oocyte and follicle development. Inhibition of MTOR induced oocyte meiotic resumption in cultured large antral follicles, as well as cumulus expansion and the expression of cumulus expansion-related transcripts in cumulus-oocyte complexes in vitro. In vivo, the activity of MTOR in cumulus cells was diminished remarkably by 4 h after hCG administration. These results thus suggest that activation of MTOR in cumulus cells contributes to the maintenance of oocyte meiotic arrest before the LH surge. Based on the observations made by us here and previously, we propose that MTOR is an essential mediator of the bi-directional communication between the oocyte and granulosa cells that regulates the development and function of both compartments.

Summary Sentence

Crosstalk mediated by mechanistic target of Rapamycin kinase between oocytes and granulosa cells is crucial for the maintenance of oocyte meiotic arrest and granulosa cell identity, promotion of oocyte competence and cumulus cell survival.

Graphical Abstract

It is estimated that approximately 25% of nonobstructive azoospermia (NOA) cases are caused by single genetic anomalies, including chromosomal aberrations and gene mutations. The identification of these mutations in NOA patients has always been a research hot spot in the area of human infertility. However, compared with more than 600 genes reported to be essential for fertility in mice, mutations in approximately 75 genes have been confirmed to be pathogenic in patients with male infertility, in which only 14 were identified from NOA patients. The small proportion suggested that there is much room to improve the methodology of mutation screening and functional verification. Fortunately, recent advances in whole exome sequencing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)–Cas9 have greatly promoted research on the etiology of human infertility and made improvements possible. In this review, we have summarized the pathogenic mutations found in NOA patients and the efforts we have made to improve the efficiency of mutation screening from NOA patients and functional verification with the application of new technologies.

Summary Sentence

We reviewed the recent advances in the identification of pathogenic mutations for nonobstructive azoospermia (NOA) and introduced how we have identified new mutations from NOA patients in our recent studies.

Infertility has become the third most common disease threatening human health, immediately after tumors and cardiovascular diseases. Male infertility is primarily caused by spermatogenesis disorders that may be classified as either genetic or non-genetic. For part of non-genetic disorders, in vitro spermatogenesis can be induced by adjusting the microenvironment of the testis culture. Establishing the in vitro spermatogenic induction system helps to clarify the critical molecular mechanisms in spermatogonia self-renewal, spermatocyte meiosis, and sperm formation during spermatogenesis. In this review, we summarize recent advances in the field of in vitro sperm cells induction. Therefore, we hope to provide ideas and solutions for the clinical treatment of male infertility.

Summary Sentence This review provides recent advances in the field of in vitro sperm cells induction and discusses potential clinical value of in vitro spermatogenesis.

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PIWI proteins and PIWI-interacting RNAs (piRNAs) are specifically expressed in animal germlines and play essential roles during gametogenesis in animals. The primary function of PIWI/piRNAs is known to silence transposable elements for protecting genome integrity in animal germlines, while their roles beyond silencing transposons are also documented by us and others. In particular, we show that mouse PIWIL1 (MIWI)/piRNAs play a dual role in regulating protein-coding genes in mouse spermatids through interacting with different protein factors in a developmental stage-dependent manner, including translationally activating a subset of AU-rich element-containing mRNAs in round spermatids and inducing massive mRNA degradation in late spermatids. We further show that MIWI is eliminated through the ubiquitin-26S proteasome pathway during late spermiogenesis. By exploring the biological function of MIWI ubiquitination by APC/C, we identified ubiquitination-deficient mutations in human PIWIL1 of infertile men and further established their causative role in male infertility in mouse model, supporting PIWIL1 as a human male infertility-relevant gene. Additionally, we reported that PIWIL1, aberrantly induced in human tumors, functions as an oncoprotein in a piRNA-independent manner in cancer cells. In the current review, we summarize our latest findings regarding the roles and mechanisms of PIWIL1 and piRNAs in mouse spermatids and human diseases, and discuss the related works in the field.

Summary Sentence

Beyond the primary function of silencing transposons, PIWI/piRNAs also play diverse roles in animal germ cells and human diseases.

Testis, the only organ responsible for generating sperm, is by far the organ with the largest variety of proteins and tissue-specific proteins in humans. In testis, spermatogenesis is a multi-step complex process well-accepted that protein and mRNA are decoupled in certain stages of spermatogenesis. With the fast development of mass spectrometry-based proteomics, it is possible to systemically study protein abundances and modifications in testis and sperm to help us understand the molecular mechanisms of spermatogenesis. This review provides an overview of the recent progress of proteomics analysis on spermatogenesis, including protein expression and multiple post-translational modifications, such as phosphorylation, glycosylation, ubiquitylation, and acetylation.

Summary Sentence

Proteomic analysis of protein expression and multiple post-translational modifications (PTMs), including phosphorylation, ubiquitylation, acetylation, and glycosylation, showed complex protein regulations in spermatogenesis and male infertility and identified biomarkers for male infertility.

Infertility affects 8–12% of couples globally, and the male factor is a primary cause in ∼50% of couples. Male infertility is a multifactorial reproductive disorder, which can be caused by paracrine and autocrine factors, hormones, genes, and epigenetic changes. Recent studies in rodents and most notably in humans using multiomics approach have yielded important insights into understanding the biology of spermatogenesis. Nonetheless, the etiology and pathogenesis of male infertility are still largely unknown. In this review, we summarized and critically evaluated findings based on the use of advanced technologies to compare normal and obstructive azoospermic versus nonobstructive azoospermic men, including whole-genome bisulfite sequencing, single-cell RNA-seq, whole-exome sequencing, and transposase-accessible chromatin using sequencing. It is obvious that the multiomics approach is the method of choice for basic research and clinical studies including clinical diagnosis of male infertility.

Summary Sentence

This review summarizes findings of the past 20 years published in literature listed in PubMed including our laboratory, utilizing multiomics approach to study the etiology and pathogenesis of male infertility.

Graphical Abstract

Testis size determination is an important question of reproductive biology. Sertoli cells are known to be a key determinant of mammalian testis size but the underlying molecular mechanisms remain incompletely understood. Previously we showed that highly conserved germ cell RNA-binding proteins, PUMILIO1(PUM1) and PUMILIO2 (PUM2), control mouse organ and body size through translational regulation, but how different cell types of the organs contribute to their organ size regulation has not been established. Here, we report a somatic role of PUM in gonad size determination. PUM1 is highly expressed in the Sertoli cells of the developing testis from embryonic and postnatal mice as well as in germ cells. Removal of Sertoli cell, but not germ cell, Pum1 gene, led to reduced testis size without significantly affecting sperm number or fertility. Knockout of PUM1 target, Cdkn1b, rescued the phenotype of reduced testis size, supporting a key role of Sertoli cell PUM1 mediated Cdkn1b repression in the testis size control. Furthermore, removal of Pum2 or both Pum1 and Pum2 in the Sertoli cells also only affected the testis size, not sperm development, with the biggest size reduction in Pum1/2 double knockout mice. We propose that PUM1 and PUM2 modulate the testis size through their synergistic translational regulation of cell cycle regulators in the Sertoli cell. Further investigation of the ovary or other organs could reveal if PUM-mediated translational control of cell proliferation of the supporting cell represents a general mechanism for organ size modulation.

Summary Sentence

PUM1 and PUM2 modulate mouse testis size through their synergistic translational regulation of cell cycle regulators in Sertoli cells.

Graphical Abstract

The prevalence of gestational diabetes mellitus (GDM) is increasing rapidly. In addition to the metabolic disease risks, GDM might increase the risks of cryptorchidism in children. However, its mechanism involved in abnormalities of the male reproductive system is still unclear. The purpose of this study was to study the effects of GDM on the development of mouse fetal Leydig cells (FLCs) and Sertoli cells (SCs). Pregnant mice were treated on gestational days 6.5 and 12.5 with streptozotocin (100 mg/kg) or vehicle (sodium citrate buffer). Leydig cell and SC development and functions were evaluated by investigating serum testosterone levels, cell number and distribution, genes, and protein expression. GDM decreased serum testosterone levels, the anogenital distance, and the level of desert hedgehog in SCs of testes of male offspring. FLC number was also decreased in testes of GDM offspring by delaying the commitment of stem Leydig cells into the Leydig cell lineage. RNA-seq showed that FOXL2, RSPO1/β-catenin signaling was activated and Gsk3β signaling was inhibited in GDM offspring testis. In conclusion, GDM disrupted reproductive tract and testis development in mouse male offspring via altering genes related to development.

Summary Sentence

The development of mouse fetal Leydig and Sertoli cells was inhibited in male offspring of gestational diabetes mothers via altering FOXL2, RSPO1/β-catenin signaling, and Gsk3β signaling.

Graphical Abstract

Although hundreds of knockout mice show infertility as a major phenotype, the causative genic mutations of male infertility in humans remain rather limited. Here, we report the identification of a missense mutation (D136G) in the X-linked TAF7L gene as a potential cause of oligozoospermia in men. The human aspartate (D136) is evolutionally conserved across species, and its change to glycine (G) is predicted to be detrimental. Genetic complementation experiments in budding yeast demonstrate that the conserved aspartate or its analogous asparagine (N) residue in yeast TAF7 is essential for cell viability and thus its mutation to G is lethal. Although the corresponding D144G substitution in the mouse Taf7l gene does not affect male fertility, RNA-seq analyses reveal alterations in transcriptomic profiles in the Taf7l (D144G) mutant testes. These results support TAF7L mutation as a risk factor for oligozoospermia in humans.

Summary Sentence

A sequencing screen of infertile men identifies a missense mutation in the human TAF7L gene.

During male meiosis, the constitutively unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI), and the DNA damage response (DDR) pathway is critical for MSCI establishment. Our previous study showed that UHRF1 (ubiquitin-like, with PHD and ring finger domains 1) deletion led to meiotic arrest and male infertility; however, the underlying mechanisms of UHRF1 in the regulation of meiosis remain unclear. Here, we report that UHRF1 is required for MSCI and cooperates with the DDR pathway in male meiosis. UHRF1-deficient spermatocytes display aberrant pairing and synapsis of homologous chromosomes during the pachytene stage. In addition, UHRF1 deficiency leads to aberrant recruitment of ATR and FANCD2 on the sex chromosomes and disrupts the diffusion of ATR to the XY chromatin. Furthermore, we show that UHRF1 acts as a cofactor of BRCA1 to facilitate the recruitment of DDR factors onto sex chromosomes for MSCI establishment. Accordingly, deletion of UHRF1 leads to the failure of meiotic silencing on sex chromosomes, resulting in meiotic arrest. In addition to our previous findings, the present study reveals that UHRF1 participates in MSCI, ensuring the progression of male meiosis. This suggests a multifunctional role of UHRF1 in the male germline.

Summary Sentence

UHRF1 is directly interacts with BRCA1 and has critical role in meiotic sex chromosome inactivation (MSCI).

Graphical Abstract

Epigenetic regulations play a central role in governing the embryo development and somatic cell reprogramming. Taking advantage of recent advances in low-input sequencing techniques, researchers have uncovered a comprehensive view of the epigenetic landscape during rapid transcriptome transitions involved in the cell fate commitment. The well-organized epigenetic reprogramming also highlights the essential roles of specific epigenetic regulators to support efficient regulation of transcription activity and chromatin remodeling. This review briefly introduces the recent progress in the molecular dynamics and regulation mechanisms implicated in mouse early embryo development and somatic cell reprograming, as well as the multi-omics regulatory mechanisms of totipotency mediated by several key factors, which provide valuable resources for further investigations on the complicated regulatory network in essential biological events.

Graphical Abstract

In recent years, the developmental origins of diseases have been increasingly recognized and accepted. As such, it has been suggested that most adulthood chronic diseases such as diabetes, obesity, cardiovascular disease, and even tumors may develop at a very early stage. In addition to intrauterine environmental exposure, germ cells carry an important inheritance role as the primary link between the two generations. Adverse external influences during differentiation and development can cause damage to germ cells, which may then increase the risk of chronic disease development later in life. Here, we further elucidate and clarify the concept of gamete and embryo origins of adult diseases by focusing on the environmental insults on germ cells, from differentiation to maturation and fertilization.

The embryos attach and invade the uterus, establishing the connection with their mother in peri-implantation development. During this period, the pluripotent epiblast cells of the embryo undergo symmetry breaking, cell lineage allocation, and morphogenetic remodeling, accompanied by the dramatic changes of transcriptomic, epigenomic, and signaling pathways, and preparing the stage for their differentiation and gastrulation. The progress in mouse genetics and stem cell biology has advanced the knowledge of these transformations, which are still largely hindered by the hard accessibility of natural embryos. To gain insight into mammalian peri-implantation development, much effort has been made in the field. Recently, advances in the prolonged in vitro culture of blastocysts, the derivation of multiple pluripotent stem cells, and the construction of stem cell-based embryo-like models have opened novel avenues to investigate peri-implantation development in mammals, especially humans. Combining with other emerging new technologies, these new models will substantially promote the comprehension of mammalian peri-implantation development, thus accelerating the progress of reproductive and regenerative medicine.

Summary Sentence

This review highlights the in vitro models for the investigation of mammalian peri-implantation embryogenesis.

The peri-implantation period from blastula to gastrula is one of the crucial stages of human embryo and stem cell development. During development, human embryos undergo many crucial events, such as embryonic lineage differentiation and development, structural self-assembly, pluripotency state transition, cell communication between lineages, and crosstalk between the embryo and uterus. Abnormalities in these developmental events will result in implantation failure or pregnancy loss. However, because of ethical and technical limits, the developmental dynamics of human peri-implantation embryos and the underlying mechanisms of abnormal development remain in a “black box.” In this review, we summarize recent progress made toward our understanding of human peri-implantation embryogenesis based on extended in vitro cultured embryos and stem cell–based embryoids. These findings lay an important foundation for understanding early life, promoting research into human stem cells and their application, and preventing and treating infertility. We also propose key scientific issues regarding peri-implantation embryogenesis and provide an outlook on future study directions. Finally, we sum up China's contribution to the field and future opportunities.

Summary Sentence

In vitro cultured human embryos and various stem cell-based embryo models can be used to deconstruct human development during peri-implantation.

Graphical Abstract

Pluripotent stem cells (PSCs) harbor the capacity of unlimited self-renewal and multilineage differentiation potential, which are crucial for basic research and biomedical science. Establishment of PSCs with defined features was previously reported from mice and humans, while generation of stable large animal PSCs has experienced a relatively long trial stage and only recently has made breakthroughs. Pigs are regarded as ideal animal models for their similarities in physiology and anatomy to humans. Generation of porcine PSCs would provide cell resources for basic research, genetic engineering, animal breeding, and cultured meat. In this review, we summarize the progress on the derivation of porcine PSCs and reprogramed cells and elucidate the mechanisms of pluripotency changes during pig embryo development. This will be beneficial for understanding the divergence and conservation between different species involved in embryo development and the pluripotent-regulated signaling pathways. Finally, we also discuss the promising future applications of stable porcine PSCs. Even though challenges remain in the field of porcine stem cells, these progress and viewpoints would provide guidance in future research direction.

The induction of primordial germ-like cells (PGCLCs) from pluripotent stem cells (PSCs) provides a powerful system to study the cellular and molecular mechanisms underlying germline specification, which are difficult to study in vivo. The studies reveal the existence of a species-specific mechanism underlying PGCLCs between humans and mice, highlighting the necessity to study regulatory networks in more species, especially in primates. Harnessing the power of single-cell RNA sequencing (scRNA-seq) analysis, the detailed trajectory of human PGCLCs specification in vitro has been achieved. However, the study of nonhuman primates is still needed. Here, we applied an embryoid body (EB) differentiation system to induce PGCLCs specification from cynomolgus monkey male and female PSCs, and then performed high throughput scRNA-seq analysis of approximately 40 000 PSCs and cells within EBs. We found that EBs provided a niche for PGCLCs differentiation by secreting growth factors critical for PGCLC specification, such as bone morphogenetic protein 2 (BMP2), BMP4, and Wnt Family Member 3. Moreover, the developmental trajectory of PGCLCs was reconstituted, and gene expression dynamics were revealed. Our study outlines the roadmap of PGCLC specification from PSCs and provides insights that will improve the differentiation efficiency of PGCLCs from PSCs.

Summary Sentence

This study outlines the roadmap of monkey primordial germ-like cells (PGCLCs) specification from pluripotent stem cells by single cell ribonucleic acid sequencing analysis and provides insights for improving the differentiation efficiency of PGCLCs.

Graphical Abstract

Haploid embryonic stem cells are embryonic stem cells of a special type. Their nuclei contain one complete set of genetic material, and they are capable of self-renewal and differentiation. The emergence of haploid embryonic stem cells has aided research in functional genomics, genetic imprinting, parthenogenesis, genetic screening, and somatic cell nuclear transfer. This article reviews current issues in haploid stem cell research based on reports published in recent years and assesses the potential applications of these cells in somatic cell nuclear transfer, genome imprinting, and parthenogenesis.

Summary Sentence

Haploid embryonic stem cells represent a powerful tool for life science research that can be used in genetic screening, functional genomics, somatic cell nuclear transfer, parthenogenesis, and heterozygous cell research.

Considerable improvements have been made to gene editing technology, which has been increasingly applied to research involving humans. Nevertheless, human heritable germline genome editing is associated with a series of potential ethical, legal, and social risks, which have generated major controversies and discussions worldwide, especially after the “gene-edited babies” incident. Influenced by this incident, China has realized the importance of ethical governance in the field of life science and technology, has accelerated legislative and policy efforts in this field, and has gradually moved toward the direction of “precautionary” ethical governance. Black letter analysis, big data public opinion analysis, and other research methods are used in this paper. This paper explores the scientific background, ethical debates, and latest developments regarding China's regulatory framework for human germline gene editing after the “gene-edited babies” controversy and provides several recommendations on the future governance system of human germline gene editing in China. This paper argues that in recent years, the ethics governance of germline genome editing in China has been accelerated and great changes have been made. However, the regulatory system for germline genome editing requires further improvement in three aspects: coordination of legislation and agencies, establishment of an ethics review system at high levels, and public participation and education.

Summary Sentence

Continual progress has been made in establishing a governance system of ethical issues regarding human genome editing, particularly human germline genome editing; however, further improvements are required.

Graphical Abstract

Wilms' tumor 1 (Wt1) encodes a zinc finger nuclear transcription factor which is mutated in 15–20% of Wilms' tumor, a pediatric kidney tumor. Wt1 has been found to be involved in the development of many organs. In gonads, Wt1 is expressed in genital ridge somatic cells before sex determination, and its expression is maintained in Sertoli cells and granulosa cells after sex determination. It has been demonstrated that Wt1 is required for the survival of the genital ridge cells. Homozygous mutation of Wt1 causes gonad agenesis. Recent studies find that Wt1 plays important roles in lineage specification and maintenance of gonad somatic cells. In this review, we will summarize the recent research works about Wt1 in gonadal somatic cell differentiation.

Summary Sentence

Wt1 is indispensable for somatic cell differentiation and gonad development at different developmental stages.

Meiosis is the foundation of sexual reproduction, and crossover recombination is one hallmark of meiosis. Crossovers establish the physical connections between homolog chromosomes (homologs) for their proper segregation and exchange DNA between homologs to promote genetic diversity in gametes and thus progenies. Aberrant crossover patterns, e.g., absence of the obligatory crossover, are the leading cause of infertility, miscarriage, and congenital disease. Therefore, crossover patterns have to be tightly controlled. During meiosis, loop/axis organized chromosomes provide the structural basis and regulatory machinery for crossover patterning. Accumulating evidence shows that chromosome axis length regulates the numbers and the positions of crossovers. In addition, recent studies suggest that alterations in axis length and the resultant alterations in crossover frequency may contribute to evolutionary adaptation. Here, current advances regarding these issues are reviewed, the possible mechanisms for axis length regulating crossover frequency are discussed, and important issues that need further investigations are suggested.

Summary Sentence

The loop-axis organization of meiotic chromosomes provides the structural basis for crossover regulation, which contributes to evolutionary adaptation.

Graphical Abstract

As an evolutionarily conserved process, the bouquet stage during meiosis was discovered over a century ago, and active research on this important stage continues. Since the discovery of the first bouquet-related protein Taz1p in 1998, several bouquet formation-related proteins have been identified in various eukaryotes. These proteins are involved in the interaction between telomeres and the inner nuclear membrane (INM), and once these interactions are disrupted, meiotic progression is arrested, leading to infertility. Recent studies have provided significant insights into the relationships and interactions among bouquet formation-related proteins. In this review, we summarize the components involved in telomere-INM interactions and focus on their roles in bouquet formation and telomere homeostasis maintenance. In addition, we examined bouquet-related proteins in different species from an evolutionary viewpoint, highlighting the potential interactions among them.

Summary Sentence

Telomere-INM interaction components that facilitate bouquet formation and telomere homeostasis are essential for meiotic progression in most eukaryotes.

The placenta is the interface between the fetal and maternal environments during mammalian gestation, critically safeguarding the health of the developing fetus and the mother. Placental trophoblasts origin from embryonic trophectoderm that differentiates into various trophoblastic subtypes through villous and extravillous pathways. The trophoblasts actively interact with multiple decidual cells and immune cells at the maternal–fetal interface and thus construct fundamental functional units, which are responsible for blood perfusion, maternal–fetal material exchange, placental endocrine, immune tolerance, and adequate defense barrier against pathogen infection. Various pregnant complications are tightly associated with the defects in placental development and function maintenance. In this review, we summarize the current views and our recent progress on the mechanisms underlying the formation of placental functional units, the interactions among trophoblasts and various uterine cells, as well as the placental barrier against pathogen infections during pregnancy. The involvement of placental dysregulation in adverse pregnancy outcomes is discussed.

Summary Sentence

We summarize recent progresses on the regulatory mechanisms involved in the formation of placental functional units, including maternal–fetal material exchange, blood perfusion, endocrine, immune adaptation, and defense barrier against infection.

The placenta is a unique organ that forms during gestation and supports fetus survival and communication with the mother. However, of such an essential organ for a successful pregnancy, our knowledge is limited. New progress has been made for human placenta study in recent years. We herein summarize the current understanding of human placental trophoblast differentiation and the molecules that govern trophoblast cell lineage specification. More importantly, the powerful tools for placental studies are also described such as human trophoblast stem cells, 3-dimensional (3D) trophoblast organoids, engineering-based placental devices, and single-cell RNA sequencing. These advances have brought us new insights into placental development and provided multiple investigation strategies for deciphering molecular mechanisms.

During pregnancy, maternal decidual tissue interacts with fetal trophoblasts. They constitute the maternal-fetal interface responsible for supplying nutrition to the fetus. Uterine natural killer (uNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy and play critical roles throughout pregnancy. This review provides current knowledge about the functions of uNK cells. uNK cells have been shown to facilitate remodeling of the spiral artery, control the invasion of extravillous trophoblast (EVT) cells, contribute to the induction and maintenance of immune tolerance, protect against pathogen infection, and promote fetal development. Pregnancy-trained memory of uNK cells improves subsequent pregnancy outcomes. In addition, this review describes the distinct functions of three uNK cell subsets: CD27^–CD11b^–, CD27⁺, and CD27^–CD11b⁺ uNK cells.

Embryo implantation is one of the hottest topics during female reproduction since it is the first dialogue between maternal uterus and developing embryo whose disruption will contribute to adverse pregnancy outcome. Numerous achievements have been made to decipher the underlying mechanism of embryo implantation by genetic and molecular approaches accompanied with emerging technological advances. In recent decades, raising concepts incite insightful understanding on the mechanism of reciprocal communication between implantation competent embryos and receptive uterus. Enlightened by these gratifying evolvements, we aim to summarize and revisit current progress on the critical determinants of mutual communication between maternal uterus and embryonic signaling on the perspective of embryo implantation to alleviate infertility, enhance fetal health, and improve contraceptive design.

Summary Sentence

We revisit the progress on the critical determinants of mutual communication between maternal uterus and embryonic signaling on the perspective of embryo implantation and aim to advance the mechanism study of embryo implantation and ultimately alleviate infertility, enhance fetal health, and improve contraceptive design.

Triclosan is a broad-spectrum antibacterial agent and widely exists in environmental media and organisms. Triclosan exposure has been reported to have adverse effects on reproduction including embryo implantation disorder. During the embryo implantation window, it is vital that the endometrium develops into a receptive state under the influence of ovarian hormones. However, the effect of triclosan on embryo implantation and endometrial receptivity remains unclear. In the current study, we found a decreased embryo implantation rate, serum estrogen, and progesterone levels in mice exposed to triclosan from gestation days 0.5 to 5.5. Through RNA sequencing (RNA-seq), we identified nearly 800 differentially expressed genes, which were enriched in various pathways, including uterus development, inflammatory response, and immune system processes. Among those enriched pathways, the tight junction pathway is essential for the establishment of the receptive state of the endometrium. Then, genes involved in the tight junction pathway, including Cldn7, Cldn10, and Crb3, were validated by quantitative real-time polymerase chain reaction and the results were consistent with those from RNA-seq. Through immunofluorescence staining and western blotting, we confirmed that the tight junction protein levels of CLDN7 and CRB3 were increased. All these findings suggest that preimplantation triclosan exposure reduces the rate of embryo implantation through upregulating the expression of the tight junction genes and affecting the receptivity of the endometrium. Our data could be used to determine the sensitive time frame for triclosan exposure and offer a new strategy to prevent implantation failure.

Summary Sentence

Preimplantation triclosan exposure affects the receptivity of the endometrium by upregulating the expression of tight junction genes, thus reducing the rate of embryo implantation.

Graphical Abstract

Well-designed birth cohorts are able to estimate prevalence/distribution of various health events/outcomes, and to link early-life origins with adult health and function. The past two decades have seen a surge in the establishment of new birth cohorts and their accompanying research. We discussed distinct designs of current birth cohort studies, reviewed their achievements, and highlighted insights obtained from birth cohort studies, as well as challenges we are facing. Birth cohort studies are providing increasing opportunities to identify determining factors for short- and long-term health, yielding substantial evidence to uncover biological mechanisms of diseases and phenotypes, and providing further insights for public health. Dynamic monitoring, accurate measurements, long-term follow-ups, and collaborative efforts are warranted in new birth cohorts to elucidate the nature of life course relationships in contemporary generation.

Summary Sentence

This review provided a summary on progress of birth cohort studies, and highlighted future challenges and perspectives.