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In mammals, ejaculated sperm must undergo complicated physiological and functional changes as they traverse the female reproductive tract before they can bind to the zona pellucida, undergo the acrosome reaction, and fertilize the egg. The preparatory changes are collectively referred to as capacitation. Capacitated sperm show hyperactivation, which is a specialized movement of the sperm flagellum that creates the propulsive force for the penetration of the zona pellucida. Changes in sperm associated with capacitation include alterations in surface properties, plasma membrane properties, ionic metabolism, cyclic nucleotide metabolism and protein phosphorylation. Elucidation of the detailed mechanism of capacitation would enable the development of the sperm function assay and the treatment of male infertility.
Mammalian sperm are highly polarized in order to accomplish their physiological function, fertilization. Sperm flagellar movement is activated on ejaculation into the extracellular environment. Sperm motility becomes hyperactivated during “capacitation”, which is required for fertilization. For mammalian sperm, ATP supplementation is essential for not only maintaining flagellar motility but also for regulating the phosphorylation events relating motility and fertilization. It was believed that oxidative phosphorylation worked mainly to provide ATP because of sperm morphological characteristics and the efficiency of ATP production. However, recent studies revealed that glycolysis in the principal piece works as the major process for supplying ATP, since glycolysis enzymes are localized to the principal piece, some of them are tightly associated with the cytoskeletal structure in it. We observed that extracellular glucose was highly utilized for the entire flagellar bending motion with a high beat frequency compared with pyruvate, a substrate for respiration. In this review, we discuss how glycolysis regulates sperm motility and function in the mouse.
An average human ejaculate contains over one hundred million sperm, but only a few succeed in accomplishing the journey to an egg by migration through the female reproductive tract. Among these few sperm, only one participates in fertilizing an egg. Surely there must be an ingenious molecular mechanism to ensure that the very best sperm succeed in fertilization. Recent gene manipulation approaches in mice have revealed that many factors previously described as important for fertilization are largely dispensable; however, novel factors are also emerging. For example, sperm from six different gene-disrupted mouse lines (Calmegin, Adam1a, Adam2, Adam3, Ace and Pgap1) are all known to have defective zona binding ability and at the same time lose oviduct migrating ability. Concerning gamete fusion, we found essential factors, IZUMO1 on sperm and CD9 on the egg, in genedisruption experiments. More recently, the structure, localization, and interacting proteins of IZUMO1 are gradually being elucidated. Besides IZUMO1, in non-mammal eukaryotes, fertilization-related proteins (GCS1 for plants and Sneaky for the fly) have been identified and reported to function in gamete interaction and fusion. This review focuses on the interactions of fusion-related proteins on sperm (the egg proteins will be discussed by Miyado et al.) of gene manipulated animals.
In fertilization, two types of gametes - sperm and egg-unite via a stepwise approach to create a fertilized cell, which is capable of naturally developing into a new individual. Notably, “membrane fusion” occurring intercellularly between a sperm and an egg is essential for fertilization. In mammals, sperm-egg fusion is, at least in part, mediated by two integral membrane proteins, sperm Izumo and egg CD9, and their roles are critical but unelucidated. A recent study showed that CD9-containing vesicles are released from wild-type eggs, and then exosome-like vesicles induce fusion between sperm and CD9-deficient eggs in vitro, even though CD9-deficient eggs are highly refractory to spermegg fusion. This result provides compelling evidence for the crucial involvement of CD9-containing, fusion-facilitating vesicles in sperm-egg fusion, and offers a new insight into gamete fusion and other membrane fusion events.
At fertilization, mammalian eggs show repetitive transient [Ca2+]i rises each of which is due to Ca2+ release from the endoplasmic reticulum through inositol 1,4,5-trisphosphate (IP3) receptors. During fertilization, a factor from the sperm, the sperm factor, is released into the oocyte and induces a long-lasting series of Ca2+ spikes (Ca2+ oscillations) that are required for egg activation. IP3-producing enzyme phospholipase C zeta (PLC) is a strong candidate for the sperm factor. The Ca2+ spikes initiate the extrusion of cortical granules that block the entry of other sperm. At the same time, maturation (M-phase) promoting factor (MPF) is inactivated by the Ca2+ oscillations, resulting in exit from metaphase II arrest. Meiosis resumes with formation of the second polar body and complete meiotic division, one-cell embryos with the male and female pronuclei attain the first cleavage division through nuclear envelope breakdown.
Continuation of the spermatogenic process throughout life relies on proper regulation of selfrenewal and differentiation in spermatogonial stem cells. Mouse spermatogonial stem cells can be cultured with established methods; however, human spermatogonial stem cells are not well understood. Recent reports have shown that adult cells can be reprogrammed to pluripotency if specific genes are delivered and almost established assay. These cells are called iPS (induced pluripotent stem) cells. In addition, it has been reported that pluripotent stem cells can be generated from adult human testes. Stem cell science has progressed remarkably quickly over the last 5 years. Future research into stem cells may reveal the mechanisms underlying male infertility and allow for patient-specific treatments. In this review, we provide an overview of the current understanding of human spermatogonial stem cells and pluripotent stem cells from adult human testes.
In recent years, assisted reproductive technology (ART) has undergone marked development and has come to play a central role in reproductive medicine. Although controlled ovarian stimulation (COS) has also improved, assessment of the ovarian reserve has become important for further improving stimulation. Existing methods of ovarian reserve assessment are inadequate, and antiMüllerian hormone (AMH) has recently garnered attention as a marker for ovarian reserve. AMH is not influenced by the menstrual cycle, can be measured at any time by collecting blood, and correlates very strongly with the number of eggs collected during in vitro fertilization. Whereas basal FSH (a conventional marker) changes after actual decreases in ovarian reserve, AMH enables quantitative prediction of ovarian reserve and is important for determining strategies for fertility treatment. Many infertile patients have AMH levels close to zero and are potential cases of premature ovarian failure. As the number of elderly infertile patients is increasing rapidly and fertility treatment is shifting from the reproductive stage to the non-reproductive stage, markers that are unstable during menopause, such as basal FSH and E2, are becoming unreliable. AMH is expected to play an increasingly important role and may become a routine test in fertility treatment.
Serotonin (5-HT) is a well-known neurotransmitter, which has been investigated as a key molecule in mental diseases. Several previous studies have reported a stimulatory effect of 5-HT on gonadal maturation via the pituitary gland in some decapods and there is some evidences that 5-HT can regulate the secretion of gonadotropin. Moreover, 5-HT itself has been found reported in both rat and human ovaries as well as follicles as measured by HPLC. To examine the possibility that 5-HT can be secreted from follicular tissues, we investigated mouse follicles for three key serotonergic components, namely, 5-HT itself, the rate-limiting enzyme of its production, TPH-1, and the serotonin synthesis enzyme, DDC. Using a combination of immunohistochemisty analysis and ELISA, we showed that mouse primordial follicles contain 5-HT and its localization was detected in the zone pellucida in the late stages. In addition, serotonin contents increased with the maturation processes. On the other hand, the gene expression of serotonin-synthesis enzymes increased during mouse follicle developments. Our results show that 5-HT may have essential roles for in the maturation of follicles and that 5-HTproducing cells, as yet unidentified, may exist in the ovary.
Polycystic ovary syndrome (PCOS) is the most common etiology of menstrual disorders and hyperandrogenism, and The understanding of PCOS has advanced significantly. However, a fully convincing animal model for study of polycystic ovaries, or of PCOS, has not been established in the mouse. In the present study, polycystic ovary (PCO) was induced by a single intraperitoneal injection of testosterone propionate (TP; 0.1 mg, dissolved in sesame oil) in female mice at 4–5 days of age. The mice exhibited either constant estrus or diestrus for 5 weeks after TP administration, and this resulted in anovulatory polycystic ovaries. These ovaries contained multiple large follicles and no corpus luteum. The morphology and ovulatory failure were similar to those of the PCOs of humans and other animals. In these ovaries, we found that only the oocytes in the secondary follicles had the following cytological changes: first meiotic division metaphase, second meiotic division metaphase, parthenogenesis and fragmentation. This mouse model has potential for application in studies of folliculogenesis and the mechanism of androgen-induced PCO.