Gametogenesis, the focus of this article, refers then to the process where female and male germs cells are formed. The sustenance of any species is dependent on its ability to reproduce. While some organisms replicate via asexual reproduction, humans and other mammals are dependent on sexual reproduction for the propagation of their species. In order for their genetic code to be passed on from parents to their offspring, specialized sex cells are produced to facilitate this process.
- What is gametogenesis
- General gametogenesis
- Oogenesis and follicular maturation
- Clinical significance
What is gametogenesis
Gametogenesis is an intricate process that involves numerous biochemical pathways and morphological changes. These sex cells are produced by a specialized type of cell replication known as meiosis. The subsequent gametes contain half the genetic information as their parent cells, and are also unique when compared with both the parent cells and among each other. This article will review the process of gametogenesis (with emphasis on sex specific differences), the neurohormonal pathways involved in the process, and some complications that can arise during the process.
Chromatin, chromosomes and gametes
The genetic code that determines sex, height, eye color, and other variable phenotypic expressions are stored as chromatin molecules. These are a series of deoxyribonucleic acid molecules that are arranged in unique sequence. All this genetic information is condensed within the nucleus of each cell by tightly coiling the chromatin around proteinaceous scaffolds known as histones. In somatic cell lines, there are twenty-three pairs of chromosomes; giving a total number of 46 chromosomes. Chromosomes 1 to 22 occur in duplicates; the remaining two chromosomes are known as sex chromosomes X and Y.
Considering that the formation of a zygote (single cell that forms after fertilization) requires the fusion of two cells; the preceding cells must have half the total number of chromosomes that should be in a somatic cell. Therefore, specialized sex cells known as gametes are produced through the process of meiosis.
Meiosis is a form of cell division that results in the production of four unique haploid cells (containing 23 chromosomes) from one diploid cell (contains 46 chromosomes). This is different from general cell division known as mitosis that produces two identical diploid cells from one diploid cell. Meiosis occurs in two stages (meiosis I and II); each containing a specialized form of prophase, metaphase, anaphase and telophase. Interphase is only observed in the first phase of meiosis.
Prior to interphase, when the cell is in the growth phase, the DNA exists as either euchromatin or heterochromatin. However, during interphase, there is condensation of the chromatin strands into visible pairs of chromosomes. Each chromosome contains a pair of sister chromatids attached at a centromere. This phase also represents a period of cellular growth where the cell constituents are duplicated in preparation for cell division. Therefore the parent cell has changed from the diploid state (having 46 chromosomes) to a tetraploid state (having 92 chromosomes; i.e. 46 pairs of chromosomes).
Following interphase, the cell enters into a convoluted yet precisely orchestrated series of events which are categorically referred to as prophase I. In general, this phase involves alignment of homologous pairs of chromosomes and exchange of genetic material. However, there are several steps required to complete this process. Therefore prophase I has been subdivided into five sub-stages:
- The leptotene stage marks the beginning of exchange of genetic information. A maternal and paternal copy of the same chromosome (each possessing two sister chromatids joined at the centromere) finds each other inside the nucleus. Further condensation of the chromosomes is also observed. Additionally, the telomeres of each chromosome become attached to the nuclear envelope.
- The homologous pairs of chromosomes become intimately attached to each other near the telomere region. The point of attachment is referred to as a synapsis; and the overall process marks the zygotene stage. As the synapses form, they often cluster to one side of the nucleus. This arrangement is occasionally referred to as a bouquet as the chromosomes are situated similar to a bouquet of flowers. The bivalent chromosomes are held together by the synaptonemal complex. Sex chromosomes (X and Y) are unpaired in males. Therefore the synapsis occurs at the pseudoautosomal region; which is an area of shared DNA sequence between these chromosomes. Hypercondensation of the sex-specific components of the chromosome results in the formation of a sex vesicle. The synapses are important for genetic recombination; which contributes to the diversification of the gene pool. At the points of fusion, genetic information is exchanged between fused chromatids. Here the synapses are referred to as chiasmata or knots that will hold the chromosomes together.
- Once all the chromosomes have formed their synapses, then the cell has entered the pachytene stage. Although there are four chromatids within each bivalent, in this stage they appear as a single structure joined at the synaptonemal complex. Recombination is completed during this phase.
- Dissolution of the synaptonemal complexes (not the chiasmata) marks the onset of the diplotene stage. Exchange of maternal and paternal genetic information has occurred and the chromosomes appear shorter than before. Of note, this stage occurs as early as the 5th gestational week in females. Their gametes then arrest in diplotene until the onset of puberty, where one primary oocyte will complete meiosis each month prior to the onset of their menstrual cycle.
- Diakinesis is analogous to the prometaphase of mitosis. The bivalents are attached to spindle fibres and begin to line up along the equatorial plate of metaphase.
Metaphase I of meiosis is very similar to the process observed in mitosis. The spindle microtubules attach to homologous pairs of chromosomes and align them along the equator of the spindles. The centromere associated with the chromatid pair points in the direction of the spindle fibre. The bivalents are then separated towards opposite poles. The only thing holding the homologues together are the chiasmata near the telomeres.
Final separation of the bivalent occurs during anaphase I as the chiasmata is untied and the homologous pairs are separated to opposite poles of the cell.
Telophase I varies between males and females. Cytoplasmic division in females occurs asymmetrically and produces a small polar body and a much larger primary oocyte. In males, the cell division is incomplete and spermatocytes retain a cytoplasmic bridge. Although the resultant cells are diploid, they are not identical to the parent cells that produced them.
Meiosis II ensues shortly after the completion of telophase I. No DNA replication occurs during this phase. This ensures that the resultant cells will have half the genetic material as the parent cells. The rest of the division is quite similar to that of mitosis. The sister chromatids are aligned with the centromeres in metaphase II; and in anaphase II, they are separated along the spindle fibres to the opposite poles of the cell. Therefore, telophase II results in the production of four genetically unique haploid cells.
The development and maturation of spermatocytes (also called sperms) is known as spermatogenesis. Unlike their female counterparts, male gametogenesis only begins at the onset of puberty. Under the influence of gonadotropin releasing hormone from the hypothalamus, the pituitary gland releases both luteinizing and follicle stimulating hormones. Luteinizing hormone acts on Leydig cells of the testicles that subsequently secrete testosterone.
Testosterone, along with follicle stimulating hormone, will stimulate the sertoli cells of the testes; leading to the production of inhibin as well as the upregulation of testosterone binding globulin receptors. Upregulation of the receptors allows further stimulation of the cells by testosterone, resulting in activation of spermatogenesis. Of note, testosterone (acting on the hypothalamus and anterior pituitary gland) and inhibin (acting on the anterior pituitary gland) forms a negative feedback loop that results in reduction of gonadotropin releasing, luteinizing and follicle stimulating hormones secretion.
The activity of the sertoli cells result in the activation and mitotic proliferation of previously dormant spermatogonia within the seminiferous tubules of the testes. They are converted to primary spermatocytes, which then enter the above mentioned first meiotic division.
The resultant secondary spermatocytes then enter the second meiotic division, which terminates with the production of four haploid spermatids. Maturation of the spherical spermatids into tadpole-like spermatocytes is referred to as spermiogenesis. This process involves elongation of the cell body and reduction in the cytoplasmic volume. The mature spermatocytes are comprised of:
- A head that contains the haploid nucleus and the acrosome that contains proteolytic enzymes needed for fertilization. Note that the acrosome is a derivative of the Golgi apparatus of the spermatid.
- A neck that forms a bridge between the head and tail.
- A tail (divided into middle, principal and end pieces) that facilitates motility. It also houses the mitochondria that produce adenosine triphosphate (ATP) for cellular motility.
Spermatocytes migrate from the lumen of the seminiferous tubules to the epididymis via peristaltic movements. Here, they are stored and continue to mature. Genetically, there are two types of spermatocytes. They all contain 22 copies of autosomes (i.e. non-sex chromosomes) and either an X or a Y chromosome (the nomenclature used is 23, X or 23, Y).
The final stage of maturation of spermatocytes occurs post-ejaculation. Within the uterus or fallopian tubes, both the seminal protein and glycoprotein coatings are stripped from the acrosome of the sperm. It is believed that the cells of the female genital tract facilitate this process. Post capacitation, spermatocytes are not able to fertilize a secondary oocyte.
Oogenesis and follicular maturation
During the antenatal period there is mitotic proliferation of oogonia (primordial oocytes). There is subsequent increase in the size of these cells, at which point they are recognized as primary oocytes.
Earlier it was mentioned that females commence gametogenesis by the 5th gestational week but the cells are arrested in early prophase I. The primary oocytes are encircled by a simple squamous layer of follicular (granulosa) cells. They secrete oocyte maturation inhibitor, which prevents the primary oocyte from completing meiosis. Together, they are referred to as the primordial follicle. By the time a female is born, they possess approximately 2 million primordial follicles.
No new primary oocytes will be produced after females are born. Majority of these primordial follicles will degenerate, leaving approximately 400,000 primary oocytes by the onset of puberty. Of these cells, only about 400 will mature during her reproductive lifetime (i.e. from menarche to menopause). There is continued growth of the primary oocyte in the peripubertal period. There is concurrent evolution of the flat follicular cells into firstly cuboidal, then columnar cells. The cells also produce an amorphous, fenestrated, glycoprotein substance called zona pellucida that surrounds the primary oocyte. Generally, only one primordial cell will mature each month during the menstrual cycle (there are some exceptions as observed with maternal twins).
As was observed in their male counterparts, the onset of puberty in females heralds the release of gonadotropin releasing hormone from the hypothalamus. It acts on the anterior pituitary gland, which releases luteinizing and follicle stimulating hormone in a similar manner. The follicular stimulating hormone acts on the granulosa cells, resulting in the production of estrogen hormones. Estrogen continues to act on the granulosa cells, driving their proliferation and stratification around the oocyte.
As the follicle begins to increase in size, the outer connective tissue cells become more organized and form the theca folliculi. These cells separate into an inner theca interna (vascular layer with glandular function) and an outer theca externa (capsular layer). Luteinizing hormone acts on the theca interna, resulting in the production of androgens. The granulosa cells subsequently convert the androgens into more estrogen hormones.
The theca interna produces pockets of follicular fluid that subsequently coalesce to form the antrum. These events coincide with morphological changes in the follicle, such that it appears more oval in shape and the oocyte are displaced towards a random pole of the follicle (forming the cumulus oophorus). This overall structure is now referred to as a secondary follicle. The primary oocyte would have also increased in size and completed meiosis I. There is unequal distribution of the cytoplasm and its constituents among the two resulting cells. As a result, the product of this division is a relatively large secondary oocyte and a redundant first polar body.
Following ovulation, the secondary oocyte progresses through meiosis II up to the point of metaphase II; at which point it is arrested until fertilization of the oocyte occurs. Once fertilized, a second polar body will be released and both are extruded from the mature oocyte. While spermatocytes have a fifty percent chance of being either 23, X or 23, Y, all the progeny of oogenesis have a 23, X genome. However, they are still genetically unique when compared to each other and to the parent cell due to random genetic assortment and genetic exchange from chiasmata formation.
Assessment of the human genome can be achieved by karyotyping. During this process, the cells are lysed and the chromosomes can be assessed microscopically with the aid of fluorescent tagging. This will increase the likelihood of detecting any abnormality that may be present. The genotype is usually expressed as the total complement of chromosomes and the combination of sex chromosomes present. Therefore, a genetically normal individual may have a karyotype that reads 46, XY (for males) or 46, XX (for females).
As is the case with any biological process, there is the potential for errors to happen during gametogenesis. The resultant cells may or may not be capable of combining to form a viable embryo. The most likely points at which errors can occur are during prophase I and anaphase of meiosis. The abnormalities occurring from prophase I are non-aneuploidy abnormalities. This means that the total number of chromosomes within the zygote is normal; however there may be a micro- or macro-deletions of a chromosome. Non-aneuploidies can occur as a result of the following processes:
- Deletions can occur resulting in the loss of varying portions of a chromosome. An example of this is Cri-du-chat syndrome where there is a macro-deletion of the petite (p) arm of chromosome 5. Patients born with this syndrome have a high risk of death before the onset of adulthood. They may also present with microcephaly and other developmental disabilities.
- Duplications can also occur such that a segment of a chromosome is replicated and reattached to the terminal segment.
- There are several types of inversion abnormalities that can occur during replication. The two most studied forms include:
- Type 1 inversions occur when there is a break in the chromosome, it reciprocates and reinserts into a region on the chromosome. Reversal of the genetic information alters the transcription and translation processes, resulting in defective protein synthesis.
- Type 2 inversions are either pericentric (involving the centromere) or para-centric (restricted to one chromosome arm, but adjacent to the centromere). The former result in changes in the arm length ratios of the chromosome, while the latter does not.
- There are also two major types of translocation that may arise during meiosis:
- A Robertsonian translocation occurs among acrocentric chromosomes. These are chromosomes with their centromeres extremely close to the telomeric end of the p arm of the chromosome (chromosomes 13, 14, 15, 21, 22 are acrocentric). The end result is such that there is loss of the p arms and the q arms fuse.
- Reciprocal translocations, however, can involve any two non-homologous chromosomes. There is complete exchange of a significant portion of the chromosomes. A common example is the Philadelphia chromosome observed in chronic myeloid leukemia. Here, a segment of chromosome 9 is attached to chromosome 22 and vice versa (t9;22).
The abnormalities that occur during anaphase of meiosis are referred to as aneuploidies. These arise as there is a failure of bivalents to separate – a phenomenon described as an anaphase lag – resulting in non-disjunction. Subsequently, there will be cells that either have too much or too little genetic information. Aneuploidies resulting in increased genetic information are more likely to survive than those with too little information. Most of these aneuploidies result in syndromic presentation as multiple systems can be affected by the extra genetic information. Some common aneuploidies include:
- Trisomy 21 (Down Syndrome) – 47, XX or XY,+21
- Trisomy 18 (Edward Syndrome) – 47, XX or XY, +18
- Trisomy 13 (Patau Syndrome) – 47, XX or XY, +13
- Turner Syndrome – 45, X
- Klinefelter Syndrome – 47, XXY
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