Human spermatozoa take 74 days to complete their development. Discuss the developmental significance of the process by breaking this period down into the main stages of spermatogenesis, describing them in relation to where in the male reproductive tract these stages are found.
The ability of a species to reproduce is a characteristic seen across every domain of life, and is responsible for the creation of every biological organism to date. In humans, this process requires the production of functional gametes, of which spermatozoa are the male counterpart. Spermatogenesis is a cellular process describing the development of an undifferentiated diploid cell, developing through a series of distinct morphological changes and stages, all pivotal for the generation of fully functional and mature haploid spermatozoa.(1)(2)
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Before spermatozoa can be distinguished as fully mature and functional gametes, the germ cell lineage must be established, and starts with the primordial germ cells (PGCs). In mice, a cluster of cells was first identified at approximately 6.5 day’s post coitum (dpc) by Chiquoine in 1954 (3), which at 10 dpc, migrates from the embryonic ectoderm, through the invaginating hind gut towards the gonadal ridge, the prospective location of the future gonads. (4) In men, the PGCs reside on the basement membrane of the seminiferous tubules of the testes, which develop during gestation.(5)(6) Here they remain quiescent until birth, after which the stem cells proliferate by mitosis, forming the spermatogonial stem cells (SSCs) also referred to as the A single (As) spermatogonia. As cells lack heterochromatin in the nucleus, thus are considered the simplest and most primitive subclass of spermatogonia. They can be further divided into ADark, which form the reserve stem cells, or APale, the progenitors of sperm cells.(2) When the latter described AS cell type divides, two identical Apr cells form, that can either complete cytokinesis to give 2 As clones or, remain linked by an intercellular bridge, which after another division, will form a synctium of 4 Aal cells, all derived from the same progenitor SSC.(1)(7) The decision whether to remain As cell or begin differentiation is thought to be influenced by the presence of Glial derived neurotrophic factor, secreted from the Sertoli cells.(2)These cells are now considered to be committed, and will continue to divide mitotically to form chains that contain 8, 16 Aal cells.(9) Hereafter, these interlinked cells transform into A1 spermatogonia, a process believed to controlled by various extrinsic factors, including retinoic acid and gonadotrophins, the absence of which results in halted progressive development of the undifferentiated SSCs.(7) The A1 cells differentiate further into A2, A3, and A4 spermatogonia with each subsequent mitotic division respectively, the latter of which can go on to mature into intermediate and type B spermatogonia, characterized by the presence of a heterochromatin in the cell’s nucleus, thus illustrating a more differentiated state of cell state. This 16-day process generating B-spermatogonia from SSCs is referred to as spermatocytogenesis, the completion of which enables the transition to the next sequential stage where meiosis dominates. (1)(8)(9)
The diploid B-spermatogonia divide mitotically creating two daughter cells, referred to as preleptotene spermatocytes. These primary spermatocytes replicate their DNA, then leave the basal compartment of the tubules by disturbing the tight junctions between Sertoli cells, and move apically into the adluminal intratubular compartment.(2) The first meiotic prophase of the spermatocytes is then initiated, and involves homologous recombination of genetic information from each sister chromatid. After the completion of this initial meiotic prophase, the cell will progress through the further meiotic stages and cytokinesis, to produce two secondary spermatocytes, a short living group of cells that rapidly enter a second meiotic phase. This 24-day process culminates in the creation of four round haploid spermatids, still cytoplasmically linked from each single primary spermatocyte. (1)(2)
To form the recognizable spermatozoa which are no longer linked by cytoplasmic bridges, specific morphological changes must occur throughout the 24-day process called spermiogenesis.(1)(10) Necessary alterations include the generation of an acrosomal vesicle, facilitated by the production of glycoprotein-rich lysosomal-like granules by the Golgi apparatus within the spermatid cell. The acrosome acts as a cap atop the nuclear surface and is essential for future oocyte fertilisation. Meanwhile, the nuclear content of the cell condenses, involving transient DNA-strand breakages and subsequent repair, coincident with chromatin remodelling.(10) The neck of the sperm grows from the proximal most centriole, connecting the nucleus and tail of the spermatid. Microtubules develop from the distal centriole, and along with exterior course fibres, form the flagellum of the spermatozoon. The final phase of spermiogenesis involves the migration of the mitochondria to a position just anterior of the flagellum, thus allowing the gamete to generate ATP and propel toward the oocyte when necessary.(2)(10)
This entirety of these processes, from SSCs to spermatids, occurs in the germline epithelium of the seminiferous tubules, which lies within invaginations of Sertoli cells. This epithelium consists therefore of cells of different developmental stages, with spermatogenesis commencing at the basal germline epithelium and gradually moving apically, as the developing gametes differentiate and become more mature, culminating in their final release into the lumen at 64 days. (1)(7)(11) The ectoplasmic specialization (ES) is a testis specific form of anchoring junction that allows interaction between the spermatids and the supporting Sertoli cells. During spermiation, the spermatids are pushed towards the tubule lumen; this is believed to be mediated by microtubules associated with the ES, extending the apical end of the Sertoli cell’s cytoplasm. To finally release the spermatid, these ES junctions and intercellular bridges between the cells must dissolve, and cytoplasm retract, allowing luminal flow to gradually pull the spermatid free. The residual body of the now ‘liberated’ spermatozoa is then digested by the Sertoli cells by phagocytosis.(11)(12) Errors during this release in spermiation result in spermatozoa degenerating, thus affecting sperm production fertility.(12) From the lumen, it takes a further 10 days for the spermatozoa to be transported, with the luminal fluid, to the epididymis via the rete testis completing the 74-day cycle. These final days of the spermatogenic process allow further elongation, maturation and acquisition of full motility.(1)(11)(12)
In order to ensure continual sperm production, the initiation of SSCs mitosis in different tubules must be intermittent as opposed to all together. A staggered pattern of spermatogenesis occurring throughout the testis enables sperm production and fertility are continuous, not periodic. (2). Within a tubule of most mammalian species, cross-sectional studies showed that germ cells in different stages of spermatogenesis are found together. Such that all the SSCs in that tubule entered mitosis and will progress through spermatogenesis en masse, irrespective of other tubules. This arrangement defines a cyclic process, referred to as the cycle of seminiferous epithelium, where a single stage of spermatogenesis occupies a linear section of the tubule, with all cells within this area being of the same stage.(2)
Neighbouring tubule segments represent a different developmental stage, such that a linear sequence of the 6 spermatogenic stages is seen progressively throughout the tubule; a spatial arrangement referred to as the spermatogenic wave, which alongside the temporal arrangement of the spermatogenic cycle enabling continuous sperm production.
Recent morphological microscopy studies have confirmed Clermont’s (15) initial suggestion of 6 distinct cellular associations, designated using Roman numerals I-VI. (14)(17) As opposed to linear segments seen on other species, a helical arrangement of multiple spirals of spermatogenic waves is thought to exist in humans. Such that, at any given cross-section, multiple segments of germ cells with different cellular associations are seen alongside one another, as depicted in Figure 1.(7) Figure 2 illustrates the entire 74 day spermatogenic process, across generations of development, and its relation to the different cellular associations seen. A positive correlation is seen between the number of stages per tubule cross section and a greater amount of sperm produced each day, hypothesized to be caused by a greater yield of SSCs divisions during early spermatogenesis.(16)
Figure 1. Human seminiferous tubule cross section. (17)
This diagram depicts a cross section of a human seminiferous tubule, wedges of the tubules constituting a stage of development, as opposed to a linear segment seen in other species. Typically, 2-4 cellular associations are seen together.
Figure 2. Spermatogenesis in humans, figure copied from (17), based on (18)(19).
An illustration representing the full cycle of spermatogenesis from 0 to 74 days, constituting 4.6 full cycles of the seminiferous epithelium, designated using Roman numerals, Depicted is the progression of progenitor spermatogonia cells through each of the developmental stages of spermatogenesis, culminating in a spermatozoa completing spermiation. At each stage of spermatogenesis, the developing cell will progress through the 6 stages seen in a cycle of the seminiferous epithelium, differentiating and acquiring cellular associations of a more developed spermatogonia. This time-frame was producing through intratesticular injection of 3H-thymidine during synthesis, with cellular progression tracked using autoradiograms. (18)(19)
Early foetal steroidogenesis is under maternal endocrine control. The 3rd trimester however, signifies the activation of the hypothalamic-pituitary-gonadal axis, an endocrine control centre active until the male is 6 months old, and quiescent until reactivation during puberty.(13) Pulsatile release of gonadotrophin releasing hormone (GnRH) from the hypothalamus provoke both Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) to be secreted from the anterior hypophysis, via the binding of GnRH to receptors on the pituitary gonadotropes, critical for spermatogenesis.(1) Neonatally, FSH activity induces the development and proliferation of the Sertoli cells in the seminiferous tubules, major supportive cells for the developing future spermatozoa. During puberty and subsequent adult male life, FSH binds to receptors on the basolateral surface Sertoli cells, activating various signalling pathways that promote the transcription of downstream genes, necessary for spermatogenesis. Glycoporteins secreted by Sertoli cells facilitate the transport of ions and hormones, and the production of proteases needed for cellular remodelling during spermatogenesis and spermiation.
During gestation and puberty, LH binds to receptors found on the Leydig cells in the intertubular tissue of the testes, stimulating the production of testosterone. Only during puberty however do mature Sertoli cells express this androgen’s receptor, so can therefore respond to the pulsatile release of testosterone. Testosterone is pivotal for maintaining the blood-testis barrier, adhesion between the Sertoli cells and spermatids, and spermiation.(2)
The significance of endocrine control for spermatogenesis, specifically its absence, can be seen in males suffering from hypogonadotropic hypogonadism; characterized by immature Sertoli cells and impaired spermatogenesis due to GnRH deficiency, with the testes remaining in a pre-pubertal state.(13)
The production of mature spermatozoa from PGCs is a highly intricate process, consisting of 4 main and distinct stages. Starting in the basal membrane of seminiferous tubules in spermatocytogenesis, these cells undergo meiosis and structurally develop all the necessary cellular associations as they move through the adluminal compartment in spermiogenesis, to be finally released into the tubule lumen in spermiation. The continual production of mature sperm is enabled through the cycle of seminiferous epithelium, giving a specific display of both temporal and spatial arrangements.(2) Tight regulation by the hypothalamic-pituitary-gonadal axis and control through feedback loops are essential for each stage of this process; errors in endocrine control are significant for the development and functionality of the gametes, and thus, implicates future fertility of the males. (1)(13)
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