It is believed that sex determination is a biological system that establishes the progress of sexual features of a living individual 1. Consequently, causing specific morphological changes in gonads, genital ducts and Urogenital sinus. The mechanism of sex determination and gonadal development is thought to be like a series of gene expressions and protein-protein interactions. Gene products have different and variable modes of action; where, some contribute in the determination process as coworkers while others have substantial and extensive roles to play2,3.
Mainly, sex determination is genetic. At the time of fertilization, the father inherits either an X or a Y chromosome to the embryo; where, at this time the genetic sex of the embryo is brought about 2. From another point of view, some genes are known to have a crucial role in determining the sex of the developing embryo. On this occasion, the SRY gene has a decisive and critical role in male sex determination. DMRT, DAX 1 and SOX 9 are also known to have their significant job in the process of sex determination 4. Mutations in these key genes can induce deficiencies or flaws during sex determination. In addition, some cases have proven that determining the sex can be a temperature dependant process.
Bipotential Primordium formation
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During the 7th to the 8th week of mammalian embryo development, the gonads are found to be in a bipotential state where, both the Wolffian and Mullerian ducts (The male and female precursors for reproductive tracts) are present 4. It has been proven that Sf1, Wt1, Emx2, Lim1 and M33 genes have an assured function in the primary phases of Primordium gonad development 5. This was achieved through the observation of the null mutant phenotypes characterizing these genes. It revealed defects in kidney and gonadal development 2.
These imperfections comprise the developing of the gonads for only a short time followed by deterioration and reversion 5. In some cases, the complete absence of gonads may be the result as in mice that are homozygous for deletions in Lim1 gene 6.
Sf1 null mutant mice showed primordial gonadal development followed by apoptotic regression at 12.5 dpc in both male (XY) and female (XX) individuals 7,8.
Other several studies have been made to study the effect of mutations in these key genes on the formation of the bipotential gonad.
A default pathway
Three dissimilar cell lineages have the bipotential ability of developing as sertoli cells in the case of testes, or as follicle cells in the case of ovaries 2.
Unless a Y chromosome is inherited and with its linked Sex determining gene (SRY gene) triggering the differentiation of the bipotential gonad into testes, gonads go through a default pathway developing as ovaries 2,9.
Male and Female Sex Determination
In mammals, the development of a male is greatly dependant on the SRY gene. A transcription factor specifically assigned for testis development is encoded on it, which has a major role in male sex differentiation 10. SRY is believed to be the essential flicker for the differentiation of supporting cell lineages to sertoli cells, which presides the development and formation of further cells of the testes 11. A cascade series of events takes place after the expression of the SRY gene in the gonads (Fig.1) 3. SOX9 is an SRY-related HMG containing bOX-gene 9. It is required for testis development, involving directing the fate of sertoli cells 12. This was proven after observing sex reversals in about 75% of XY SOX9 heterozygotes, or the developing of ambiguous genetalia 13.
As a result of SRY expression in sertoli cells, SOX9 is upregulated. SOX3 is another SRY-related HMG containing bOX-gene 3. It tries to repress SOX9. As an example of the SRY vital role is that it may intervene to prevent SOX3 from inhibiting SOX9.
The fact that, some vertebrates exhibit well-maintained expression patterns of SOX9 in the ovary and testis despite the lack of SRY gene 2, opens the door for the question about the necessity of SOX9 in the early development of testis.
Fig.1. A model for the regulatory network of proteins involved in gonadogenesis. Arrows have been used to indicate where the presence of one protein positively influences the production of another. Blocked lines represent a repressive effect. Abbreviations: AMH, anti-Mullerian hormone; FGF9, fibroblast growth factor 9; GATA4, GATA-binding protein 4; HSP70, heat shock protein 70; N-CoR, nuclear receptor co repressor; SF1, steroidogenic factor 1; WT1, Wilmsâ€™ tumor gene 1.From 3 Fig.2.
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AMH (Anti Mullerian Hormone) a member of Transforming growth Factor beta (TGFÎ²) family, or also named MIS (Mullerian Inhibitory Substance) is expressed in the sertoli cells of XY gonad 7. In males, the presence of MIS leads to the development of the Wolffian duct (mesonephric duct) and the regression of Mullerian duct. Mesonephric duct development also requires Testosterone secreted by the Leydig cells. On the contrary, Mullerian duct develops in females on account of the absence of MIS 7.
FGF9 (Fibroblast Growth Factor 9) has a vital role in testicular embryogenesis. Mice lacking fibroblast growth factor unveil male-to-female sex reversal 14. It appears that Fgf9 acts in the same direction with Sry to induce sertoli cells differentiation 7.
DMRT1 is expressed in XY and XX gonads at early stages. Furthermore, its expression becomes constrained to the testis 15. It maps to a cluster of DMRT genes located on chromosome 9 7. XY null mutant mice for Dmrt1 develop normal testis in the beginning, subsequently reveal seminiferous tubules deterioration at later stages. On the other hand, XX null Dmrt1 mice develop normal ovaries 16.
Consequently, the need of DMRT1 in the early gonadal sex-determination juncture is doubtful.
Gene duplication in DAX1 caused XY Dosage Sensitive Sex Reversal (DSS) 11. Accordingly, it may be concluded that DAX1 effectively suppresses the SRY action. As an evidence for that, Dax1 null male mice exhibit sterility and Leydig cells hyperplasia 2.
Further studies and observations revealed a number of Key genes and factors responsible for many actions in sex determination and gonadal development (see Table.1) 7.
Table.1. From7 Table.1.
Temperature-dependant sex determination (TSD)
Even though sex determination is mainly chromosomal (CSD) in mammals, in many reptiles sex determination is temperature dependant owing to the temperature of egg incubation 17. Reptiles, crocodiles, turtles and alligators are excellent examples to study sex determination as a temperature dependant process 18.
In 1970s, TSD was proven to be prevalent among reptiles by the several studies done on various species of lizards and turtles 19.
An important term is the Transition range(s) of temperature (TRT) which is characteristic to species. It is defined as the temperature at which the possibility of obtaining males or females is equal 19. Temperature is believed to affect sex determination during the Temperature sensitive period (TSP). TSP relates to the early stages of gonadal development 19. Aromatase is a key gene in TSD where its expression is affected by the change in temperature during the TSP 20.
Temperature has to be taken in consideration when talking about sex determination. Further work and studies about temperature and human sex determination could come in handy in order to have a better understanding about how temperature affects sex determination.
To sum up, it is agreed that sex determination is a multi-step procedure. It starts with the differentiation of genetic sex, followed by the gonadal sex and ending with the body sex where secondary sexual characteristics develop. The presence or absence of a Y chromosome determines only the genetic sex which is the first step. It is pivotal but cannot be the only factor determining the sex of the embryo. SRY gene encoded on the Y chromosome is only a trigger for a cascade series of events controlled by a group of genes and factors. Any malfunction or mutation in this series of events may cause sex reversal or abnormalities in gonadal development.
A lot of studies act as evidences for the fact that; the absence of one or more gene or factor regulating the male-sex determination pathway causes the orientation of a gonad to develop by default as female. There is a group of non Y-chromosomal genes that have to work in a normal manner for the process to continue in the right direction.
What is more, Temperature should not be missed as one of the factors affecting sex determination in some species.
In a nut shell, sex determination is not a single switch process. It cannot be only a matter of X and Y chromosomes.
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