BIO178 Lecture 5 Summer24 PDF

Lecture 5: Sex Determination and Sexual Differentiation  Announcements 1. Quiz #2 PDF is up; due Friday by 11:59pm 2. Quiz #1 Key will be up tomorrow; turn it in today for partial credit if you haven’t yet. 3. No lecture or discussion this Thursday! (4th of Ju...

Lecture 5: Sex Determination and Sexual Differentiation  Announcements 1. Quiz #2 PDF is up; due Friday by 11:59pm 2. Quiz #1 Key will be up tomorrow; turn it in today for partial credit if you haven’t yet. 3. No lecture or discussion this Thursday! (4th of July holiday) 4. My office hours: Tues/Wed 11am-12pm (zoom link in syllabus) **Or by appointment if you can’t make it! 2  Outline of Today’s Lecture 1. Overview of Sexual Differentiation 2. Differentiation of the Gonads 3. Differentiation of the Internal Reproductive Tract 4. Differentiation of the External Genitalia 5. Disorders of Sexual Differentiation a) Disorders in Chromosomal Females b) Disorders in Chromosomal Males 3  Learning Objectives By the end of today’s lecture, you should be able to… 1. Describe the process of sex determination in mammals. 2. Describe the determinants and processes of sexual differentiation of the gonads, internal reproductive tract, and external genitalia in mammals. 3. Explain what can go wrong with sex determination and sexual differentiation in humans, and explain the consequences of these disorders and the mechanisms underlying these consequences. 4 Overview of Sex Determination and Sexual Differentiation  Sexual Differentiation: Overview Sex Determination The event that determines whether an individual will become male or female. Sexual Differentiation The developmental process of becoming male or female. 6  Sexual Differentiation: Overview What is sex? Chromosomal sex Gonadal sex **These are the levels of sex - and they all contribute to an Gametic sex organism’s sexual phenotype. Hormonal sex Morphological sex Behavioral sex Gender identity Gender role Legal sex 7  Sexual Differentiation: Overview Jost’s Model of Sexual Differentiation Genetic Gonadal Phenotypic Sex Sex Sex Hormones Non-hormonal factors 8 Differentiation of the Gonads Sexual Differentiation: Overview Jost’s Model of Sexual Differentiation Normal Sexual Differentiation Undifferentiated gonad Chromosomal sex Gonadal sex Sexual phenotype 10  Gonadal Differentiation Germinal (gonadal) ridge: Thickened ridge of tissue on surface of each mesonephros (protokidney) Bipotential tissue: Can develop into either a testis or an ovary Meso- nephros Germinal ridge Primordial germ cells 11  Gonadal Differentiation SRY Gene (Sex-determining Regions of the Y chromosome) On tip of Y chromosome; codes for SRY transcription factor (also known as TDF, testis determining factor) Major target of SRY is Sox9, gene coding for SOX9 (another transcription factor). - SOX9 leads to differentiation of Sertoli cells. - Sertoli cell actions direct the remainder of testicular differentiation. This pathway determines differentiation of testes in therian (placental and marsupials) mammals, including humans. - This means that, for mammals, embryos develop as female by default. 12 Genes on the Human Y Chromosome 13 Monotremes, such as platypuses, can have up to 20 sex chromosomes. 14 Gonadal Differentiation Eggers et al. 2014 15  Gonadal Differentiation SRY Gene XY phenotypic females can have mutations in SRY XX phenotypic males often have SRY-containing translocation to X chromosomes 16  Gonadal Differentiation Ovary-determining Genes Genes in ovarian differentiation not well understood Foxl2 - Transcription factor essential for ovarian development Two X chromosomes necessary for normal ovarian development Eggers et al. 2014 17  Gonadal Differentiation Antagonism between testis-determining genes and ovary-determining genes (each can switch off the other) 18 Eggers et al. 2014  Gonadal Differentiation Germinal ridge is initially indifferent/bipotential; contains a medulla and cortex. SRY expression → inner medulla develops into testis. No SRY expression → outer cortex develops No Sry Sry into ovary. SRY acts locally – not blood-borne. In mammals, gonadal steroids have only minor effects on differentiation of gonads! Human fetal testes Human fetal ovaries 19 Differentiation of the Internal Reproductive Tract Sexual Differentiation: Overview Jost’s Model of Sexual Differentiation Normal Sexual Differentiation Undifferentiated gonad Chromosomal sex Gonadal sex Sexual phenotype 21  Reproductive Tract Differentiation Two duct systems initially present in each embryo, connecting gonads to urogenital sinus (opening to urinary and reproductive tracts during early embryonic development): Wolffian ducts Urogenital Can develop into male Sinus internal reproductive tract Müllerian ducts Can develop into female internal reproductive tract 22  Reproductive Tract Differentiation Wolffian Ducts Depend on action of testosterone. If T is present: No T T Develops into epididymis, vas deferens, and seminal vesicles. If no T is present: Ducts regress. 23  Reproductive Tract Differentiation Müllerian Ducts Depend on action of Mullerian-inhibiting- hormone (MIH; glycoprotein from testes). No MIH MIH If MIH is present: Mullerian ducts regress If no MIH is present: Development into fallopian tubes (oviducts), uterus, & cervix, 24 Reproductive Tract Differentiation 25 Silverthorn 2009 Differentiation of the External Genitalia  Differentiation of External Genitalia Bipotential precursor tissues in a fetus Genital folds & genital tubercle Identical in males and females until week 6-8 Genital folds 27  Differentiation of External Genitalia Males: In presence of Genital androgens… folds Genital tubercle → penis Androgens No Androgens Genital folds → scrotum (testes descend later) Depends on dihydrotestosterone (DHT; synthesized locally from T via 5α-reductase) 28  Differentiation of External Genitalia Females: In absence of Genital folds androgens (DHT)… Genital tubercle → clitoris Androgens No Androgens Genital folds → labia 29 Summary of Sexual Differentiation Silverthorn 2009 30 Summary of Sexual Differentiation 31  Disorders of Sexual Differentiation in Chromosomal Females  True Hermaphroditism Both ovarian and testicular tissue are present in the same individual: – Ovary on one side, testis on the other (chimerism) – Ovotestes (individual gonad contains both testicular and ovarian tissue) (Mosaicism) Rare in humans Usually 46,XX; sometimes 46,XX/46,XY chimerism or mosaicism Phenotypically variable Some are fertile as females 33  True Hermaphroditism Gonads of rabbits with CRISPR-induced mutation in SRY Song et al. 2018 34 Hermaphroditism in other animals 35  Disorders in Chromosomal Females: Turner Syndrome (XO) One X chromosome is completely or partially missing Ovaries are incompletely developed – do not produce steroid hormones Immature genital tract & external genitals; short stature; heart defects; infertility (usually) May have other abnormalities (variable phenotype) Often lethal prenatally 36  Disorders in Chromosomal Females: Triple X Syndrome (XXX) Usual symptoms: Taller than average Generally normal sexual development and usually not sterile Mental impairment Less common symptoms: Vertical folds of skin that cover the inner corners of the eyes (epicanthal folds) Widely spaced eyes Weak muscle tone (hypotonia) Seizures, problems with the kidneys, premature ovarian issues 37  Disorders in Chromosomal Females: Turner Syndrome (XO) “Streak ovaries” 38  Disorders in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH) Autosomal recessive Several different forms. Most common: Enzyme deficiency (21-hydroxylase) → fetal adrenals can’t produce cortisol so all precursor hormones get turned into androgens instead. 39  Disorders in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH) Adrenal Cortex  Androstenedione X X X  X X  Testosterone X X X X Low aldosterone Low cortisol High androgens 40  Disorders in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH) Low cortisol → decreased negative feedback to hypothalamus and anterior pituitary high CRH, high ACTH → increased stimulation of adrenal cortex → high adrenal androgens 41 42  Disorders in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH) Causes masculinization of the external genitalia (but not the internal reproductive tract) in females Can be mild to severe Can be treated with surgery and exogenous steroids 43  Disorders of Sexual Differentiation in Chromosomal Males  Disorders in Chromosomal Males: Androgen Insensitivity Syndrome (AIS) X-linked gene causes defective androgen receptors; leads to total or partial androgen insensitivity (highly variable) Complete AIS: Testes develop; Wolffian and Müllerian ducts regress; external genitalia appear female Female body type and gender identity, but sterile Incomplete (Partial) AIS: May have both male and female characteristics (e.g., enlarged clitoris) Male or female gender identity 45  Disorders in Chromosomal Males: Androgen Insensitivity Syndrome (AIS) 46  Disorders in Chromosomal Males: 5a-Reductase Deficiency No 5a-reductase – can’t convert T to DHT. XY infants have ambiguous genitalia and small, undescended testes. At puberty, high T levels masculinize the external genitals and the body. Testosterone (T) 5−Dihydrotestosterone (DHT) 19 5−Reductase 5 H 47 Disorders in Chromosomal Males: 5a-Reductase Deficiency 48  Disorders in Chromosomal Males: Trisomies 1. XXY (Klinefelter Syndrome) Phenotypically male Small testes, androgen deficiency Low sperm production (sterile) Gynecomastia Mental impairment 2. XYY Phenotypically male Normal sexual development Extremely tall Mental impairment Hyperactive Antisocial 49 End of Lecture 5 50