This article provides an overview of literature pertaining to epididymosome origin, composition and their functional significance. Broadly, epididymosomes are defined as extracellular vesicles that are secreted by the epididymal epithelium and thereafter facilitate intercellular communication within the male reproductive tract. Epididymosomes fulfil this communication role via their encapsulation and delivery of a diverse macromolecular payload to recipient cells. This complex cargo includes proteins, lipids, and nucleic acids, which are delivered to maturing spermatozoa, thereby influencing their viability and function. Additionally, epididymosomes have been implicated in the post-translational modification of intrinsic sperm proteins, protection of sperm from oxidative stress and immune surveillance, and in the transmission of epigenetic information capable of mediating intergenerational effects. Hence, continued research into the biogenesis, cargo composition, and functional significance of epididymosomes holds promise for advancing male reproductive health and fertility treatments.

The seminal vesicle contributes to a large extent of the semen volume and composition. Removal of seminal vesicle or lack of seminal vesicle proteins leads to decreased fertility. Seminal plasma proteome revealed that seminal fluid contained a wide diversity of proteins. Many of them are known to modulate sperm capacitation and serve as capacitation inhibitors or decapacitation factors. Despite identifying secretory vesicles from the male reproductive tract, such as epididymosomes or prostasomes, isolation, identification, and characterization of seminal vesicle-derived exosomes are still unknown. This chapter aims to review the current understanding of the function of seminal vesicles on sperm physiology and male reproduction and provide ultracentrifugation-based isolation protocols for the isolation of seminal vesicle exosomes. Moreover, via proteomic analysis and functional categorization, a total of 726 proteins IDs were identified in the purified seminal vesicle exosomes fraction. Preliminary data showed seminal vesicle-derived exosomes inhibited sperm capacitation; however, more studies will be needed to reveal other functional involvements of seminal vesicle-derived exosomes on the sperm physiology and, more importantly, how these exosomes interact with sperm membrane to achieve their biological effects.

Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.

The regulation of mRNA transcription and translation is uncoupled during oogenesis. The reason for this uncoupling is two-fold. Chromatin is only accessible to the transcriptional machinery during the growth phase as it condenses prior to resumption of meiosis to ensure faithful segregation of chromosomes during meiotic maturation. Thus, transcription rates are high during this time period in order to produce all of the transcripts needed for meiosis, fertilization, and embryo cleavage until the newly formed embryonic genome becomes transcriptionally active. To ensure appropriate timing of key developmental milestones including chromatin condensation, resumption of meiosis, segregation of chromosomes, and polar body extrusion, the translation of protein from transcripts synthesized during oocyte growth must be temporally regulated. This is achieved by the regulation of mRNA interaction with RNA binding proteins and shortening and lengthening of the poly(A) tail. This chapter details the essential factors that regulate the dynamic changes in mRNA synthesis, storage, translation, and degradation during oocyte growth and maturation.

DNA damage poses a significant challenge to all eukaryotic cells, leading to mutagenesis, genome instability and senescence. In somatic cells, the failure to repair damaged DNA can lead to cancer development, whereas, in oocytes, it can lead to ovarian dysfunction and infertility. The response of the cell to DNA damage entails a series of sequential and orchestrated events including sensing the DNA damage, activating DNA damage checkpoint, chromatin-related conformational changes, activating the DNA damage repair machinery and/or initiating the apoptotic cascade. This chapter focuses on how somatic cells and mammalian oocytes respond to DNA damage. Specifically, we will discuss how and why fully grown mammalian oocytes differ drastically from somatic cells and growing oocytes in their response to DNA damage.

In mammals, oogenesis initiates before birth and pauses at the dictyate stage of meiotic prophase I until luteinizing hormone (LH) surges to resume meiosis. Oocyte maturation refers to the resumption of meiosis that directs oocytes to advance from prophase I to metaphase II of meiosis. This process is carefully modulated to ensure a normal ovulation and successful fertilization. By generating excessive amounts of oxidative stress, environmental toxicants can disrupt the oocyte maturation. In this review, we categorized these environmental toxicants that induce mitochondrial dysfunction and abnormal spindle formation. Further, we discussed the underlying mechanisms that hinder oocyte maturation, including mitochondrial function, spindle formation, and DNA damage response.

The head is often considered the most complex part of the vertebrate body as many different cell types contribute to a huge variation of structures in a very limited space. Most of these cell types also interact with each other to ensure the proper development of skull, brain, muscles, nerves, connective tissue, and blood vessels. While there are general mechanisms that are true for muscle development all over the body, the head and postcranial muscle development differ from each other. In the head, specific gene regulatory networks underlie the differentiation in subgroups, which include extraocular muscles, muscles of mastication, muscles of facial expression, laryngeal and pharyngeal muscles, as well as cranial nerve innervated neck muscles. Here, I provide an overview of the difference between head and trunk muscle development. This is followed by a short excursion to the cardiopharyngeal field which gives rise to heart and head musculature and a summary of pharyngeal arch muscle development, including interactions between neural crest cells, mesodermal cells, and endodermal signals. Lastly, a more detailed description of the eye development, tissue interactions, and involved genes is provided.

The relationships between motor neurons and the skeletal muscle during development and in pathologic contexts are addressed in this Chapter.We discuss the developmental interplay of muscle and nervous tissue, through neurotrophins and the activation of differentiation and survival pathways. After a brief overview on muscular regulatory factors, we focus on the contribution of muscle to early and late neurodevelopment. Such a role seems especially intriguing in relation to the epigenetic shaping of developing motor neuron fate choices. In this context, emphasis is attributed to factors regulating energy metabolism, which may concomitantly act in muscle and neural cells, being involved in common pathways.We then review the main features of motor neuron diseases, addressing the cellular processes underlying clinical symptoms. The involvement of different muscle-associated neurotrophic factors for survival of lateral motor column neurons, innervating MyoD-dependent limb muscles, and of medial motor column neurons, innervating Myf5-dependent back musculature is discussed. Among the pathogenic mechanisms, we focus on oxidative stress, that represents a common and early trait in several neurodegenerative disorders. The role of organelles primarily involved in reactive oxygen species scavenging and, more generally, in energy metabolism-namely mitochondria and peroxisomes-is discussed in the frame of motor neuron degeneration.We finally address muscular involvement in amyotrophic lateral sclerosis (ALS), a multifactorial degenerative disorder, hallmarked by severe weight loss, caused by imbalanced lipid metabolism. Even though multiple mechanisms have been recognized to play a role in the disease, current literature generally assumes that the primum movens is neuronal degeneration and that muscle atrophy is only a consequence of such pathogenic event. However, several lines of evidence point to the muscle as primarily involved in the disease, mainly through its role in energy homeostasis. Data from different ALS mouse models strongly argue for an early mitochondrial dysfunction in muscle tissue, possibly leading to motor neuron disturbances. Detailed understanding of skeletal muscle contribution to ALS pathogenesis will likely lead to the identification of novel therapeutic strategies.

The pancreas is a dual-function organ, with exocrine cells that aid in digestion and endocrine cells that regulate glucose homeostasis. These cell types share common progenitors and arise from the embryonic ducts. Early signaling events in the embryonic ducts shape the neonatal, adolescent, and adult exocrine and endocrine pancreas. This chapter discusses recent advances in the tools used to study the ducts and our current understanding of how ductal development contributes to pancreatic organogenesis.

The existence of functionally diverse and plastic β cells in islets of Langerhans has been reported since the 1980s. Recently, high-resolution technologies have advanced our understanding of β-cell heterogeneity and plasticity. Here, we define plasticity broadly as dynamic changes in cellular phenotypes and heterogeneity as differences in cellular behaviors. Individual β cells react differently to environmental challenges and act together to maintain β-cell mass and glucose homeostasis within a narrow range of 70-140 mg/dL. During the progress of diabetes, this elaborate balance is disrupted, and a lack of β-cell compensation leads to dysregulated blood glucose. In this chapter, we assess β-cell stress that instigates increased β-cell heterogeneity and adaptive β-cell responses such as proliferation, dedifferentiation, maturity, and insulin secretion. We also discuss the maturity, electrical activity, and insulin secretion of well-characterized β-cell subgroups. Finally, we touch upon the plasticity of other non-β pancreatic cells and their cooperation with β cells to maintain homeostasis.

The pancreas has been considered a non-regenerative organ. β cells lost in diabetes are not replaced due to the inability of the pancreas to regenerate. However, ample evidence generated in the last few decades using murine models has demonstrated that the pancreas has a remarkable plasticity wherein differentiated cells can change cell fate toward a β-like cell phenotype. Although this process is observed after using rather artificial stimuli and the conversion efficiency is very limited, these findings have shed some light on novel pathways for β-cell regeneration. In this chapter, we will summarize the different cellular interconversion processes described to date, the experimental details and molecular regulation of such interconversions, and the genomic technologies that have allowed the identification of potential new ways to generate β cells.

The pancreatic β cells are at the hub of myriad signals to regulate the secretion of an adequate amount of insulin needed to re-establish postprandial euglycemia. The β cell possesses sophisticated metabolic enzymes and a variety of extracellular receptors and channels that amplify insulin secretion in response to autocrine, paracrine, and neurohormonal signals. Considerable research has been undertaken to decipher the mechanisms regulating insulin secretion. While the triggering pathway induced by glucose is needed to initiate the exocytosis process, multiple other stimuli modulate the insulin secretion response. This chapter will discuss the recent advances in understanding the role of the diverse glucose- and fatty acid-metabolic coupling factors in amplifying insulin secretion. It will also highlight the intracellular events linking the extracellular receptors and channels to insulin secretion amplification. Understanding these mechanisms provides new insights into learning more about the etiology of β-cell failure and paves the way for developing new therapeutic strategies for type 2 diabetes.

Pancreatic δ cells act locally to repress both insulin and glucagon secretion. Because they are a rare cell type, experimentation examining δ-cell function and control has lagged that of the more abundant α and β cells. Emerging evidence, enabled partly by developing single-cell technology, demonstrates that δ-cell function is, in part, directed by δ cells but that δ cells also have intrinsic control. The contribution of these cells to overall glucose homeostasis and diabetes onset and progression is still unclear. However, they regulate both α and β cells, both of which are dysfunctional in diabetes, and their numbers are disrupted in humans with diabetes and in multiple animal models of diabetes, suggesting δ cells are a pivotal character in both health and disease.

Maternal nutrition and metabolic health status during pregnancy are critical factors that shape the life-long health trajectory of offspring. Altered nutrition during specific times of development in utero can lead to functional changes in tissues such as the pancreatic β-cells, predisposing those tissues to metabolic diseases and Type 2 diabetes that manifest later in life. This chapter will focus on the role of pregnancy complications with altered nutrition during gestation in the maladaptive programming of β-cell mass and function in the offspring.

The ear serves two vital functions of hearing and maintaining balance. It achieves these roles within three major compartments: the outer, the middle, and the inner ear. Embryological development of the ear and its associated structures have been studied in some animal models. Yet, the role of skeletal muscle in ear development and its related structures is largely unknown. Research suggests the outer ear and parts of the inner ear may require skeletal muscle for normal embryogenesis. Here, we describe the role of skeletal muscle in the development of the ear and its associated structures. Moreover, we report the possible consequences of defect in the skeletal muscle of the ear and the clinical correlates of such consequences.

We summarize how skeletal muscle and lung developmental biology fields have been bridged to benefit from mouse genetic engineering technologies and to explore the role of fetal breathing-like movements (FBMs) in lung development, by using skeletal muscle-specific mutant mice. It has been known for a long time that FBMs are essential for the lung to develop properly. However, the cellular and molecular mechanisms transducing the mechanical forces of muscular activity into specific genetic programs that propel lung morphogenesis (development of the shape, form and size of the lung, its airways, and gas exchange surface) as well as its differentiation (acquisition of specialized cell structural and functional features from their progenitor cells) are only starting to be revealed. This chapter is a brief synopsis of the cumulative findings from that ongoing quest. An update on and the rationale for our recent International Mouse Phenotyping Consortium (IMPC) search is also provided.

The field of epigenetics broadly seeks to define heritable phenotypic modifications that occur within cells without changes to the underlying DNA sequence. These modifications allow for precise control and specificity of function between cell types-ultimately creating complex organ systems that all contain the same DNA but only have access to the genes and sequences necessary for their cell-type-specific functions. The pancreas is an organ that contains varied cellular compartments with functions ranging from highly regulated glucose-stimulated insulin secretion in the β-cell to the pancreatic ductal cells that form a tight epithelial lining for the delivery of digestive enzymes. With diabetes cases on the rise worldwide, understanding the epigenetic mechanisms driving β-cell identity, function, and even disease is particularly valuable. In this chapter, we will discuss the known epigenetic modifications in pancreatic islet cells, how they are deposited, and the environmental and metabolic contributions to epigenetic mechanisms. We will also explore how a deeper understanding of epigenetic effectors can be used as a tool for diabetes therapeutic strategies.

The skeletal musculature and the cartilage, bone and other connective tissues of the skeleton are intimately co-ordinated. The shape, size and structure of each bone in the body is sculpted through dynamic physical stimuli generated by muscle contraction, from early development, with onset of the first embryo movements, and through repair and remodelling in later life. The importance of muscle movement during development is shown by congenital abnormalities where infants that experience reduced movement in the uterus present a sequence of skeletal issues including temporary brittle bones and joint dysplasia. A variety of animal models, utilising different immobilisation scenarios, have demonstrated the precise timing and events that are dependent on mechanical stimulation from movement. This chapter lays out the evidence for skeletal system dependence on muscle movement, gleaned largely from mouse and chick immobilised embryos, showing the many aspects of skeletal development affected. Effects are seen in joint development, ossification, the size and shape of skeletal rudiments and tendons, including compromised mechanical function. The enormous plasticity of the skeletal system in response to muscle contraction is a key factor in building a responsive, functional system. Insights from this work have implications for our understanding of morphological evolution, particularly the challenging concept of emergence of new structures. It is also providing insight for the potential of physical therapy for infants suffering the effects of reduced uterine movement and is enhancing our understanding of the cellular and molecular mechanisms involved in skeletal tissue differentiation, with potential for informing regenerative therapies.

The primary mechanism of telomere elongation in mammals is reverse transcription by telomerase. An alternative (ALT) pathway elongates telomeres by homologous recombination in some cancer cells and during pre-implantation embryo development, when telomere length increases rapidly within a few cell cycles. The maternal and paternal telomeres in the zygote are genetically and epigenetically distinct, with differences in telomere length and in chromatin packaging. We discuss models for how these asymmetries may contribute to telomere regulation during the earliest embryonic cell cycles and suggest directions for future research.

The ability to assess various cellular events consequent to perturbations, such as genetic mutations, disease states and therapies, has been recently revolutionized by technological advances in multiple "omics" fields. The resulting deluge of information has enabled and necessitated the development of tools required to both process and interpret the data. While of tremendous value to basic researchers, the amount and complexity of the data has made it extremely difficult to manually draw inference and identify factors key to the study objectives. The challenges of data reduction and interpretation are being met by the development of increasingly complex tools that integrate disparate knowledge bases and synthesize coherent models based on current biological understanding. This chapter presents an example of how genomics data can be integrated with biological network analyses to gain further insight into the developmental consequences of genetic perturbations. State of the art methods for conducting similar studies are discussed along with modern methods used to analyze and interpret the data.

Cancer is a global public health issue and remains one of the leading causes of death in the United States (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). It is estimated in the US in 2022, about 935,000 new cases of cancer will be diagnosed in women, and the probability of developing invasive cancer is 5.8% for females younger than 50 years old (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). However, advances in screening programs, diagnostic methods, and therapeutic options have greatly increased the five-year survival rate in reproductive-age women with a variety of cancers. Given the clinical consequences of gonadotoxic cancer therapies, young, female cancer survivors may face compromised fertility, premature ovarian insufficiency, early-onset menopause, and endocrine dysregulation (Bedoschi et al. Future Oncol. 12:2333-44, 2016). Gonadotoxic side effects may include decreased oocyte quality within surviving follicles, loss of ovarian follicles, and impaired ovarian function. In reproductive-age women, oocyte quality is an important element for successful clinical pregnancies and healthy offspring as poor-quality oocytes may be a cause of infertility (McClam et al. Biol Reprod. 106:328-37, 2022; Marteil et al. Reprod Biol. 9:203-24, 2009; Krisher. J Anim Sci. 82: E14-E23, 2004). Thus, it is critical to determine the quantity and quality of surviving follicles in the ovary after cancer treatment and to assess oocyte quality within those surviving follicles as these are markers for determining the capacity for ovarian function restoration and future fertility, especially for young cancer survivors (Xu et al. Nat Med. 17:1562-3, 2011). The long-term effects of cancer therapeutics on oocyte quality are influenced by factors including, but not limited to, individual patient characteristics (e.g. age, health history, comorbidities, etc.), disease type, or treatment regimen (Marci et al. Reprod Biol Endocrinol. 16:1-112, 2018). These effects may translate clinically into an impaired production of viable oocytes and compromised fertility (Garutti et al. ESMO Open. 6:100276, 2021).