Sex determination involves the commitment of the embryo to follow either a male or female developmental pathway. The key step in this process is the development of the undifferentiated embryonic gonads into either testes or ovaries. In humans, sex is determined at the moment of fertilization by the constitution of the sex chromosomes. Two X chromosomes result in ovaries and a female phenotype while an X and Y constitution produces testes and male development.
It has been known for some time that the Y chromosome carries a dominant testis-determining gene, which causes the undifferentiated embryonic gonad to develop as a testis. The masculinizing effect of the testis results from the secretion of the hormones testosterone and anti-Müllerian hormone (AMH; also known as Müllerian inhibitory substance, MIS). AMH causes regression of the embryonic female Müllerian ducts. In the absence of the Y chromosome (and absence of the testis-determining gene), ovaries will develop. Interestingly, female development will still occur in the absence of ovaries or their hormonal products. Consequently, the decisive event in sex determination is whether or not a testis develops. In humans and other mammals, sex determination can be equated with testis determination.
This chapter describes what we know of the genes that control human gonad development and how alterations in these genes can cause sex-reversed phenotypes. The Y-linked testis-determining gene SRY and others in this complex developmental network, such as SOX9, WT1, SF1, DAX1 and DMRT1, are discussed.
Regardless of their sex, all human embryos initially develop a common set of genital structures. A pair of primordial gonads, the genital ridges, appear in both males and females during the sixth week of embryonic life. Two associated ducts develop, the Müllerian and Wollfian ducts, while presumptive external genitalia appear as folds of cloacal tissue. The fate of these undifferentiated internal and external structures depends upon the genetic sex of the embryo. In individuals with an XY sex chromosome constitution, the genital ridges become testes. Hormones released from the developing testes masculinize the internal ducts and external genitalia. Sertoli cells of the fetal testes synthesize anti-Müllerian Hormone (AMH; also known as Müllerian inhibitory substance), which induces Müllerian duct regression. Meanwhile, testosterone secretion from Leydig cells induces Wolffian duct differentiation into vas deferens, and virilization of the external genitalia into penis and scrotum. Testis differentiation is initiated by the SRY gene (sex-determining region of the Y chromosome). In individuals with an XX sex chromosome constitution, SRY is absent and the genital ridges differentiate as ovaries rather than testes. Furthermore, in the absence of AMH and testosterone, the ducts follow alternative developmental paths. In the absence of AMH, the Müllerian ducts are free to differentiate into the Fallopian tubes, uterus and upper portion of the vagina. In the absence of testosterone, the Wolffian ducts regress. The external genitalia of female embryos differentiate into clitoris and labia.
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