5 Allan Pacey and Katrina Williams Spermatozoa are haploid cells (Fawcett 1975) evolved for the purpose of delivering the male genome to the oocyte. To achieve this, they have a highly specialized structure, which is created through the complex process of spermatogenesis over about 72 days. Spermatogenesis occurs in the testicles and is responsible for producing millions of fully differentiated sperm every day (Bronson, 2011). The sperm created are specialized for the journey of traversing the female reproductive tract (Suarez and Pacey 2006) and fertilizing an oocyte. This chapter will review the process of spermatogenesis and how the structure of sperm is essential for their function. Functional mature spermatozoa are made through the process of spermatogenesis, occurring in the seminiferous tubules, situated in the testes (Sutovsky and Manandhar 2006). The first stage of spermatogenesis involves the mitotic division of nonproliferative type A spermatogonia into type B spermatogonia, which are ready to enter meiosis (Phillips et al. 2010). Type A spermatogonia can either commit to differentiate, or self‐renew, a step required in order to maintain a population of progenitor cells within the testis. Type B cells then differentiate into primary spermatocytes, which then progress through meiosis I to half their chromosomal complement and form haploid secondary spermatocytes (Figure 5.1). The final step of spermatogenesis involves a meiosis II division forming haploid round spermatids (reviewed in Wistuba et al. 2007). Figure 5.1 Cellular differentiation during spermatogenesis begins with Type A spermatogonia either committing to differentiate into Type B spermatogonia or self‐renewal. Type B spermatogonia then further differentiate into primary spermatocytes which are in prophase of meiosis I, consisting of a duplicated complement of DNA, 2n, 4c. In primary spermatocytes, homologous chromosomes line up along the metaphase plate, which allows for homologous recombination, before entering meiosis I and dividing into secondary spermatocytes, which have a haploid complement of chromosomes, with sister chromatids still bound together (1n, 2c). Meiosis I is known as a reductional division as the chromosomal complement has halved to haploid. Secondary spermatocytes then progress through meiosis II to form four round spermatids with one set of chromosomes (1n, 1c). During the final step, spermiogenesis, the round spermatids further differentiate into the specialized form that is required for a functional spermatozoa. Reproduced with permission of Ana‐Maria Tomova. Round spermatids then go through a series of morphological changes during the second stage of this process, known as spermiogenesis. During this stage, many spermatid organelles are remodelled or degraded by ubiquitin‐dependent proteolysis (Bedard et al. 2011) in order to form a functional sperm with the correct accessory structures. The Golgi apparatus is remodelled to form the acrosomal cap (Moreno et al. 2000) and the cytosol becomes the perinuclear theca (Oko 1995). It is during this step of spermatogenesis that the sperm DNA is remodelled into a more condensed structure more suitable to the function of the spermatozoon (Meistrich et al. 2003). Other features of the spermatid are removed, including half of the mitochondrial load and the nuclear pore complexes, involved in mRNA transport (Sutovsky and Manandhar 2006). Once the round spermatid is remodelled into an elongated form, the process of sperm production is concluded by the release of the sperm from the tight associations with Sertoli cells. This last step is known as spermiation. The elongated spermatid is released into the lumen of the seminiferous tubule where the sperm travel to the rete testis and continue their developmental journey through the male reproductive tract (Bronson 2011). The architecture of the testis is a complex of looped seminiferous tubules, which end in the rete testis. Spermatogenesis occurs in the epithelium of the seminiferous tubules, which is solely populated by spermatogonial and Sertoli cells (Griswold 1995). The Sertoli cells surround the germ cells, providing nutrients and are also involved in the hormonal regulation of spermatogenesis (Griswold 1998). Sertoli cells form tight junctional complexes between each cell, creating a blood–testis barrier, which divides the seminiferous epithelium into two compartments, the basal and adluminal compartments. Spermatogenesis and spermiogenesis occur whilst the spermatogonial cells are in close contact with the Sertoli cells in the basal compartment of the tubule (Griswold 1995). However, the final step of the process, spermiation, involves the release of the differentiated spermatid from the close connections with the Sertoli cells into the immune‐privileged lumen of the seminiferous tubule. The process of spermatogenesis is regulated by a complex endocrine feedback loop (reviewed in Holdcraft and Braun 2004). Gonadotropin‐releasing hormones (GnRH) secreted from the hypothalamus act on the pituitary gland. Subsequently, follicle‐stimulating hormone (FSH) is released, which acts upon Sertoli cells. The pituitary gland also releases luteinizing hormone (LH), which acts upon Leydig cells. Leydig cells are located in the interstitial space between seminiferous tubules, and upon activation with LH these cells release testosterone. Testosterone then acts upon Sertoli cells, which are involved in the differentiation of spermatogonial stem cells into the spermatozoon. After release into the lumen of the seminiferous tubule and passing through the rete testis, sperm enter the epididymis. At this point, they are incapable of fertilizing an oocyte, as they are still biologically immature. Therefore, further maturation occurs during transport through the epididymis where spermatozoa acquire fertilization capability (Moore 1998). Under the influence of epididymal secretory proteins (Brown et al. 1983), spermatozoa acquire the ability to recognize and bind to the oocyte (Hinrichsen and Blaquier 1980). They also acquire progressive motility (Dacheux et al. 1987), through activation of tyrosine phosphorylation signalling pathways (Lin et al. 2006). Upon reaching the tail (cauda) of the epididymis, the final storage place before ejaculation (Robaire and Viger 1995), spermatozoa have acquired the ability to fertilize an egg. This is in comparison to samples taken from the head (caput) of the epididymis, which are still biologically immature (Hinrichsen and Blaquier 1980; Dacheux et al. 1987). A spermatozoon consists of two major parts: the sperm head and the tail (Figure 5.2). The major components of the sperm head are the nucleus and the acrosome. The sperm tail can be further divided into four sections, which are connected by the same internal structure: first of all, the connecting piece containing the sperm centriole; the mid piece containing the mitochondria, the source of adenosine triphosphate (ATP) required for sperm motility; the principal piece; and the end piece. Figure 5.2 The structure of the human spermatozoa. The head contains the acrosome and the condensed male DNA in the nucleus. The head is connected to the tail via the mid (connecting) piece containing the centriole and the mitochondria, wrapped around the axial filament, which runs throughout the entire sperm tail. Reproduced with permission of Ana‐Maria Tomova. The nucleus contains the male DNA in a highly condensed and quiescent form (Brewer et al. 2002; Dadoune, 2003). During spermiogenesis, the histones bound to DNA are replaced by protamines, serving to protect the male genetic information. It is thought that sperm are unable to repair their own DNA (Matsuda et al. 1985), therefore the DNA needs to be protected from any factors, which might compromise its integrity. The condensation of the male DNA is also thought to serve in aiding the transit of sperm through the female reproductive tract and penetration of the oocyte outer layers (Dadoune 2003). The condensed nature of sperm DNA makes it inaccessible to enzymes and therefore it is thought that transcriptional activity and de novo gene expression is unlikely to occur. However, evidence pertaining to sperm genomics and proteomics questions this accepted theory, which will be discussed later. The sperm head also contains the acrosome, a Golgi‐derived vesicle, containing hydrolytic enzymes and receptors (Yoshinaga and Toshimori 2003), required for interaction and penetration of the oocyte zona pellucida (ZP) (Osman et al. 1989). Interaction with a ZP glycoprotein, ZP3, initiates an exocytotic reaction, resulting in the release of the acrosomal components and digestion of the ZP, allowing the sperm to penetrate this layer (Brewis et al. 1996). After penetration of the ZP, sperm enter the perivitelline space and are able to bind to the oolemma. After the acrosome reaction occurs, receptors present on the inner acrosomal membrane and at the equatorial segment are unveiled. Receptors located at the equatorial segment, such as fertilin‐β were thought to be involved in the fusion with the oolemma (Cho et al. 1998). However, it is now known that a member of a major immunoglobulin family, Izumo1, is the main receptor (Inoue et al. 2005) involved with fusion to the putative egg receptor, Juno (Bianchi et al. 2014). The remainder of the sperm head is composed of the perinuclear theca (PT), a matrix of structural proteins that provides support and confers head shape. PT proteins located in the posterior part of the sperm head, the postacrosomal segment, are thought to function in signalling during early embryogenesis once the PT is dissolved in the oocyte cytoplasm (Sutovsky et al. 1997). The sperm tail (or flagellum) provides the motile force for sperm to travel through the female reproductive tract. At the centre of the sperm tail is the microtubule axoneme. This is composed of a nine plus two arrangement of microtubule doublets, with nine symmetrically arranged outer doublets connected to the two central doublets by radial spokes (Fawcett 1975). The outer doublets are connected by dynein arms, which are the motor proteins responsible for the creation of mechanical energy from ATP (Turner 2003). Coordinated asynchronous movement of dynein arms at each microtubule doublet allows for bending of the axoneme and subsequent flagella movement (Turner 2003). Surrounding the outer doublets are nine outer dense fibres that provide flexibility and support during movement of the flagellum (Figure 5.3). Figure 5.3 The tail of the sperm contains a central skeleton, constructed of 11 microtubules collectively termed the axoneme, similar to the structure found in general cilia. Back and forth movement results from a rhythmical longitudinal sliding motion between the anterior and posterior tubules that make up the axoneme. The flagellar (tail) waveform is created by the motor activities of the axonemal dynein arms working against the stable microtubule doublets. This motion propels the sperm and ATP produced by mitochondria supplies energy for this process. Reproduced with permission of Ana‐Maria Tomova. The sperm tail can be divided into three major sections in addition to the end piece. The connecting piece contains the remaining proximal centriole, leftover from spermatogenesis (Sutovsky and Manandhar 2006
The Human Spermatozoa
Introduction
Spermatogenesis
Epididymal Maturation
The Structure of Mature Sperm
The Sperm Head
The Sperm Tail
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