Molecular Reproduction and Development最新文献

The emergence of the earliest cell lineages in mammalian embryos is a complex process that utilizes an extensive network of chromatin regulators, transcription factors, cell polarity regulators, and cellular signaling pathways. These factors and pathways operate over a protracted period of time as embryos cleave, undergo compaction, and form blastocysts. The first cell fate specification event separates the pluripotent inner cell mass from the trophectoderm lineage. The second event separates pluripotent epiblast from hypoblast. This review summarizes over 50 years of study of these early lineage forming events, addressing the complexity of the network of interacting molecules, cellular functions and pathways that drive them, interspecies differences, and aspects of these mechanisms that likely underlie their high susceptibility to disruption by numerous environmental factors that can compromise embryo viability, such as maternal health and diet, environmental toxins, and other stressors.

This review focuses on the contribution of the late David Garbers to chemotaxis of sperm, in particular from sea urchin. We will describe his discovery of chemotactic peptides and their cognate receptors, his discovery of a sperm-specific, unique Na⁺/H⁺ exchanger that represents a chimera between a solute carrier (SLC) and an ion channel. Finally, we will discuss his contributions to the understanding of cAMP signaling in sperm via soluble adenylyl cyclase (sAC) and its control by Ca²⁺ ions.

The development of novel non-hormonal male contraceptives represents a pivotal frontier in reproductive health, driven by the need for safe, effective, and reversible contraceptive methods. This comprehensive review explores the genetic underpinnings of male fertility, emphasizing the crucial roles of specific genes and structural variants (SVs) identified through advanced sequencing technologies such as long-read sequencing (LRS). LRS has revolutionized the detection of structural variants and complex genomic regions, offering unprecedented precision and resolution over traditional next-generation sequencing (NGS). Key genetic targets, including those implicated in spermatogenesis and sperm motility, are highlighted, showcasing their potential as non-hormonal contraceptive targets. The review delves into the systematic identification and validation of male reproductive tract-specific genes, utilizing advanced transcriptomics and genomics studies with validation using novel knockout mouse models. We discuss the innovative application of small molecule inhibitors, developed through platforms like DNA-encoded chemistry technology (DEC-Tec), which have shown significant promise in preclinical models. Notable examples include inhibitors targeting serine/threonine kinase 33 (STK33), soluble adenylyl cyclase (sAC), cyclin-dependent kinase 2 (CDK2), and bromodomain testis associated (BRDT), each demonstrating nanomolar affinity and potential for reversible and specific inhibition of male fertility. This review also honors the contributions of Dr. David L. Garbers whose foundational work has paved the way for these advancements. The integration of genomic, proteomic, and chemical biology approaches, supported by interdisciplinary collaboration, is poised to transform male contraceptive development. Future perspectives emphasize the need for continued innovation and rigorous testing to bring these novel contraceptives from the laboratory to clinical application, promising a new era of male reproductive health management.

Bioenergetics plays a crucial role in sperm functions, including motility, capacitation-related protein modifications, oocyte recognition and interaction, all of which are essential for fertilization. Sperm metabolism is recognized as flexible, responding to environmental cues and energetic demands during ejaculation, the journey along the female tract, and until fertilization. Recent studies suggest that sperm metabolic functions are relevant beyond fertilization and may influence zygote and embryo development, impacting paternal-derived effects on offspring development and health. In recent years, sperm metabolic functions and homeostasis have gained increasing interest in male reproduction research. Given the crucial implications of sperm metabolism on fertility-related processes, this field is of interest not only in human male fertility but also in livestock research, semen conservation, and assisted reproductive techniques. Newly developed assessment tools are allowing a better understanding of sperm metabolism under different conditions and identifying species-specific peculiarities. This review aims to discuss the current knowledge of mammalian sperm metabolism, focusing on species-specific features, changes during the sperm journey, and potential contributions to translational research and reproductive biotechnologies. Furthermore, we propose future perspectives on sperm bioenergetics research.

The actions of spermatogenic stem cells (SSCs) provide the foundation for continual spermatogenesis and regeneration of the cognate lineage following cytotoxic insult or transplantation. Several decades of research with rodent models have yielded knowledge about the core biology, morphological features, and molecular profiles of mammalian SSCs. Translation of these discoveries to utilities for human fertility preservation, improving animal agriculture, and wildlife conservation are actively being pursued. Here, we provide overviews of these aspects covering both historical and current states of understanding.

Dr. David Garbers made many impactful contributions to science and vastly improved our understanding of sperm biology. In this review, we focus on his identification of a key role for the second messenger cAMP in mammalian sperm. As a graduate student David discovered that sperm motility, which is essential for sperm to fertilize the egg, is under the control of the (at the time) recently identified, prototypical second messenger cAMP. Fast-forwarding to the present, agents which turn off sperm's ability to generate cAMP and block sperm motility are being investigated as potential nonhormonal contraceptives for men and women. Should these efforts prove successful, Dave's discoveries will prove to be the spark which ignited a revolution in human health.

Dave Garbers’ work significantly contributed to our understanding of sperm's regulated motility, capacitation, and the acrosome reaction. These key sperm functions involve complex multistep signaling pathways engaging numerous finely orchestrated elements. Despite significant progress, many parameters and interactions among these elements remain elusive. Mathematical modeling emerges as a potent tool to study sperm physiology, providing a framework to integrate experimental results and capture functional dynamics considering biochemical, biophysical, and cellular elements. Depending on research objectives, different modeling strategies, broadly categorized into continuous and discrete approaches, reveal valuable insights into cell function. These models allow the exploration of hypotheses regarding molecules, conditions, and pathways, whenever they become challenging to evaluate experimentally. This review presents an overview of current theoretical and experimental efforts to understand sperm motility regulation, capacitation, and the acrosome reaction. We discuss the strengths and weaknesses of different modeling strategies and highlight key findings and unresolved questions. Notable discoveries include the importance of specific ion channels, the role of intracellular molecular heterogeneity in capacitation and the acrosome reaction, and the impact of pH changes on acrosomal exocytosis. Ultimately, this review underscores the crucial importance of mathematical frameworks in advancing our understanding of sperm physiology and guiding future experimental investigations.