GENETICS AND BIOLOGY OF EARLY REPRODUCTIVE TRACT DEVELOPMENT
Most living species
have some form of sex-determination system that drives the development and
expression of sexual characteristics in that organism. Sex determination can be
genetic or can be a consequence of environmental or social variables. In
humans, sex determination is genetic and is governed by specific genes and
chromosomes. It is believed that the two human sex chromosomes (X and Y) evolved
from other nonsex chromosomes (autosomes) 300 million years ago. Human females
have two of the same kind of sex chromosome (XX), whereas males have two
distinct sex chromosomes (XY). However, both male and female features can
rarely be found in one individual, and it is possible to have XY women and XX men.
Analysis of such individuals has revealed the genes of sex determination,
including SRY (sex-determining region Y gene) on the short arm of the Y
chromosome, which is important for maleness. The SRY gene product is a
protein that harbors a high-mobility group box (HMG) sequence, a highly
conserved DNA-binding motif that kinks DNA. This DNA-bending effect alters gene
expression, leading to formation of a testis and subsequently to the male
phenotype. Notably, XY individuals who lack the SRY gene on the Y
chromosome are phenotypic females.
It is now
clear that the SRY gene does not act in isolation to determine human
sex. Other genes in other locations are also important for complete male sexual
differentiation. DAX1, a nuclear hormone receptor, can alter SRY activity
during development by suppressing genes downstream to SRY that would
normally induce testis differentiation. A second gene, WNT4, largely
confined to the adult ovary, may also serve as an “anti-testis” gene. Indeed,
the discovery of these genes has significantly altered theories of sex
determination. Previously, SRY gene presence was thought to determine
male gonadal development from the bipotential gonad. The female genotype was
considered the “default” developmental pathway for gonads. It is now clear that
genes such as WNT4 and DAX1 can proactively induce female gonadal
development, even in the presence of SRY.
Once
gonadal sex is determined, several other events must occur for normal male
sexual differentiation. Within the testis, Leydig cells make testosterone, a
hormone that is critical for development of the internal genitalia, including
the vas deferens, epididymis, and seminal vesicles through wolffian duct
differentiation. Leydig cells also synthesize insulin-like-3 to promote
transabdominal testis migration that begins testis descent into the scrotum.
Dihydrotestosterone (DHT), a testosterone metabolite, masculinizes the genital
anlage to form the external genitalia, including the penis and scrotum as well
as the prostate. In addition, Sertoli cells within the developing testis
synthesize anti-müllerian hormone (AMH or MIF), which prevents the müllerian duct
from developing into uterus and fallopian tubes and helps the early germ cells
remain quiescent in the developing testis. Deficiencies in any of these
developmental pathways generally results in either birth defects or intersex
disorders. Such development disorders, formerly termed true or pseudo-hermaphroditism,
can include chromosomal abnormalities, ambiguous genetalia, phenotypic sex
anomalies, or true
intersex states.
