The biological path an embryo takes toward developing male or female anatomy is determined by a carefully timed genetic signal. Early in development, all mammalian embryos possess identical, undifferentiated structures capable of forming either male or female gonads, representing a default developmental pathway. Initiating male development requires a specific genetic switch to override this default, triggering a cascade of events that directs the formation of male reproductive organs. This process hinges entirely on the presence and proper function of a single, specialized gene, which acts as the earliest and most decisive factor in sex determination.
Locating the Sex Determining Gene
The genetic instruction that initiates male development is contained within a specific sequence of DNA known as the Sex-determining Region Y gene, or SRY. This gene is located on the short arm of the Y chromosome, which is typically present in individuals with an XY chromosome complement. Like any gene, SRY serves as a blueprint, providing instructions for building a specific protein that carries out a function within the cell.
By coding for a particular protein, the SRY gene sets the stage for a chain reaction that transforms the trajectory of the developing embryo, moving it away from the neutral, or female, path.
How the SRY Protein Acts as a Master Switch
The protein produced by the SRY gene is often referred to as the Testis-Determining Factor (TDF). This molecule functions as a transcription factor, meaning its purpose is to bind directly to specific DNA sequences to regulate the activity of other genes. The SRY protein belongs to the High Mobility Group (HMG) box family of proteins, characterized by a domain that causes the DNA double helix to bend sharply upon binding.
This physical bending of the DNA is the molecular action that flips the developmental switch. By binding and bending the DNA, the SRY protein turns on a network of genes necessary for male development, most notably the SOX9 gene. Simultaneously, it suppresses genes associated with the female developmental pathway, such as Wnt4 and Foxl2. The sustained expression of SOX9 solidifies the commitment of the undifferentiated cells to become the Sertoli cells of the developing testis.
The Developmental Path to Male Anatomy
The SRY protein’s gene activation occurs in the indifferent gonad, a bipotential structure that forms around the sixth week of gestation. Once the SRY protein is produced, it triggers the cells in the gonad’s inner region, the medulla, to differentiate into the primitive testes. In the absence of SRY, the outer region, the cortex, would develop into an ovary.
The newly formed testes begin to function as an endocrine organ almost immediately, secreting two major hormones that control the rest of sex differentiation. Sertoli cells produce Anti-Müllerian Hormone (AMH), which causes the regression of the Müllerian ducts (the embryonic structures that would otherwise develop into the uterus and fallopian tubes). Leydig cells secrete testosterone. Testosterone drives the development of the Wolffian ducts into the internal male reproductive structures, including the epididymis, vas deferens, and seminal vesicles. For the external genitalia to form, testosterone is locally converted into the more potent androgen dihydrotestosterone (DHT).
When SRY Does Not Function Properly
The singular importance of the SRY gene means that any disruption to its function or location can result in a mismatch between chromosomal sex and physical anatomy. One condition arises when a segment of the Y chromosome containing SRY is accidentally transferred onto an X chromosome during sperm formation. An embryo with a 46,XX karyotype that inherits this X chromosome will possess the SRY gene and develop into a male (46,XX testicular difference of sex development). Conversely, a mutation within the SRY gene can render its protein non-functional, even in an individual with a 46,XY karyotype. If the SRY protein cannot activate the male developmental cascade, the default female pathway proceeds, leading to the indifferent gonad developing into a non-functional streak gonad or ovary (Swyer syndrome).