1 SEX DETERMINATION • Reviews: • Wilhelm D, Koopman P. • The makings of maleness: towards an integrated view of male sexual development. • Nat Rev Genet. 2006 Aug;7(8):620-31. • Kim Y, Capel B. • Balancing the bipotential gonad between alternative organ fates: A new perspective on an old problem. • Dev Dyn. 2006 Sep;235(9):2292-300. • Research papers: • Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B. • Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. • PLoS Biol. 2006 Jun;4(6):e187.!1. Genotypic sex determination 2. Environmental sex determination SEX DETERMINATION, 2 MAIN MECHANISMS ! Sex Determination!1. Chromosomal/genetic : males and females differ in one or more genes or in whole chromosomes a) Numbers of chromosome sets, e.g. haploid versus diploid as in bees b) Ratio of X chromosomes to autosomes, C-elegans: XX= hermaphrodite, XO= male Drosophila: XX=female, XY=male (but the Y is for fertility only) c) Dominant sex determining chromosome Some fish, e.g. Medaka: XX female, XY male DMY is the Y-linked male determining gene, but only in two closely related species. Some amphibians and reptiles. Birds: ZW female, ZZ male (But dosage could be involved) !! !!!! Sex Determination 2. Environmental - all individuals have the same genetic make-up, but the environment influences which sex develops, e.g. many species of fish and reptiles SPECIES MECHANISM SEXES Mouse, man CSD*: dominant Y XX female XY male Birds CSD: ratio (?) ZW female ZZmale Turtles ESD†: temperature warm = female cool = male Alligators ESD: temperature cool = female warm = male Insects: Drosophila melanogaster CSD: X/A ratio XX female XY male Musca domestica CSD: dominant M locus m/m female M/m male Apis mellifera CSD: haplo-diploidy diploid female haploid male Nematodes: Caenorhabditis elegans CSD: X/A ratio XX hermaphrodite XO male Meliodogyne incognita ESD: population density sparse = female crowded = male • CSD = chromosomal sex determination, ESD = environmental sex determination 1. Genotypic sex determination Y chromosome X chromosome 2. Environmental sex determination e.g., Turtles use temperature > 32°C produces females < 28°C produces males SEX DETERMINATION, 2 MAIN MECHANISMS2 CHROMOSOMAL SEX DETERMINATION IN MAMMALS • MAMMALS - the presence of either a second X chromosome or a Y chromosome determines whether the embryo is female (XX) or male (XY) • BIRDS - the male has two similar sex chromosomes (ZZ), while the female has the unmatched pair (ZW) • FLIES - the ratio of X chromosomes to autosomes determines sexual phenotype. • PRIMARY SEX DETERMINATION: – Establishment of chromosomal sex at fertilization – The development of the undifferentiated gonads into testis or ovaries • SECONDARY SEX DETERMINATION: – the sequential differentiation of internal and external genitalia in accordance with gonadal sex (phenotypic sex) PRIMARY AND SECONDARY SEX DETERMINATION IN MAMMALS - Y • PRIMARY SEX DETERMINATION: 1. Establishment of chromosomal sex at fertilization 2. The development of the undifferentiated gonads into testis or ovaries 1. ESTABLISHMENT OF CHROMOSOMAL SEX AT FERTILIZATION - The Y chromosome carries the testis determining factor. This factor will organize the gonad into a testis rather than an ovary. The mammalian Y chromosome is a crucial factor for determining sex in mammals ???? Evidence for the Y chromosome mechanism: 1. Y chromosome confers maleness and determines sex. 2. Verified by studies of non-disjunction aneuploidy: XO “Turner Syndrome” Female Sterile 1/10,000 Survivors show below average height, poorly developed breasts, and immature sexual organs XXY “Klinefelter Syndrome” Male 1/1000 Above average height, under-developed testes, and breast development in ~50% XYY-Male with above average height, fertility problems. XXX-Female, normal though sometimes less fertile. 1. ESTABLISHMENT OF CHROMOSOMAL SEX AT FERTILIZATION 2. DEVELOPMENT OF THE GONAD The indifferent gonad develops in the context of the larger urogenital system. Three overlapping, sequential kidney systems: the pronephros, the mesonephros and the metenephros. The three regions develop in an anterior to posterior direction along the Wolffian duct. The kidney is a product of the interaction between the metanephric mesenchype and the ureteric bud.3 A second duct, the Mullerian duct, originates within the mesonephors by invagination of the coelemic epithelium. This duct runs parallel to the Wolfian duct but turns toward the midline at the posterior end of the mesenophros. The gonads arise from a thickening in the ventrolateral surface of each mesonephros. During this indifferent stage, the genital ridge epithelium proliferates and extends into the loose connective mesenchymal tissue above it. These epithelial layers form the SEX CORDS. The germ cells migrate into the gonad and are surrounded by the sex cords. DEVELOPMENT OF THE GONAD TESTIS DEVELOPMENT If the fetus is XY, the sex cords continue to proliferate extending deeply into the connective tissue. These cords form a network of internal sex cords and at the most distal end, the thinner rete testes. Eventually the cord, now call testis cords, lose contact with the surface epithelium and become separated from it by a thick extracellular matrix, the tunica albugnia. When germ cells enter the male gonads, they will develop in these testis cords. TESTIS DEVELOPMENT The testis cord will differentiate into Sertoli cells which secrete anti-Mullerian hormone and later support the development of sperm. At puberty the cords hollow out to form the seminiferous tubules and the germ cells migrate to the periphery and differentiate. In the mature seminiferous tubule, the sperm are transported from inside the testis through the rete testis. These tubules will link the testis to the Wolfian duct, which differentiates into the epididymus and vas deferes, the tube through which the sperm pass into the urethra. During development interstitial mesenchymal cells differentiate into Leydig cells which make testosterone. OVARIAN DEVELOPMENT In females, the germ cells will reside near the outer surface of the gonad. Unlike the sex cords in