Talk:BGD Lecture - Sexual Differentiation
References
--Mark Hill 11:26, 28 May 2011 (EST) This is a good recent review paper from one of the original researchers who discovered SRY. Listed below the reference are links to the review figures in various formats.
<pubmed>17237341</pubmed>| Physiol. Rev.
Figure Pages
These are links to the images with descriptive legends.
- Signaling in genital development
- Sex reversal in humans caused by abnormal X-Y exchange
- Mesonephric tubules in the 11.5 dpc mouse urogenital ridge
- Development and differentiation of the genital duct system
- The migratory pathway of primordial germ cells
- Structure of the early fetal testis
- Differentiation of pre-Sertoli cells into Sertoli cells
- Model for cell-autonomous and prostaglandin-mediated upregulation of Sox9 in pre-Sertoli cells
- Visualization of testicular cell types
- Ovary and follicle development and differentiation
- Postulated molecular pathway leading to the formation of the bipotential genital ridge
- Structure of mouse and human SRY protein
- Postulated interaction of molecular players involved in early testicular development
Table 1. Genes implicated in sexual development in mammals
Figures
These are links to just the images.
- Fig. 1 - Signaling in genital development
- Fig. 2 - Sex reversal in humans caused by abnormal X-Y exchange
- Fig. 3 - Mesonephric tubules in the 11.5 dpc mouse urogenital ridge
- Fig. 4 - Development and differentiation of the genital duct system
- Fig. 5 - The migratory pathway of primordial germ cells
- Fig. 6 - Structure of the early fetal testis
- Fig. 7 - Differentiation of pre-Sertoli cells into Sertoli cells
- Fig. 8 - Model for cell-autonomous and prostaglandin-mediated upregulation of Sox9 in pre-Sertoli cells
- Fig. 9 - Visualization of testicular cell types
- Fig. 10 - Ovary and follicle development and differentiation
- Fig. 11 - Postulated molecular pathway leading to the formation of the bipotential genital ridge
- Fig. 12 - Structure of mouse and human SRY protein
- Fig. 13 - Postulated interaction of molecular players involved in early testicular development
Table 1. Genes implicated in sexual development in mammals
Figure Pages and Figures
These are links to the figure pages with descriptive legends and the images alone.
- Signaling in genital development | Fig. 1 - Signaling in genital development
- Sex reversal in humans caused by abnormal X-Y exchange | Fig. 2 - Sex reversal in humans caused by abnormal X-Y exchange
- Mesonephric tubules in the 11.5 dpc mouse urogenital ridge | Fig. 3 - Mesonephric tubules in the 11.5 dpc mouse urogenital ridge
- Development and differentiation of the genital duct system | Fig. 4 - Development and differentiation of the genital duct system
- The migratory pathway of primordial germ cells | Fig. 5 - The migratory pathway of primordial germ cells
- Structure of the early fetal testis | Fig. 6 - Structure of the early fetal testis
- Differentiation of pre-Sertoli cells into Sertoli cells | Fig. 7 - Differentiation of pre-Sertoli cells into Sertoli cells
- Model for cell-autonomous and prostaglandin-mediated upregulation of Sox9 in pre-Sertoli cells | Fig. 8 - Model for cell-autonomous and prostaglandin-mediated upregulation of Sox9 in pre-Sertoli cells
- Visualization of testicular cell types | Fig. 9 - Visualization of testicular cell types
- Ovary and follicle development and differentiation | Fig. 10 - Ovary and follicle development and differentiation
- Postulated molecular pathway leading to the formation of the bipotential genital ridge | Fig. 11 - Postulated molecular pathway leading to the formation of the bipotential genital ridge
- Structure of mouse and human SRY protein | Fig. 12 - Structure of mouse and human SRY protein
- Postulated interaction of molecular players involved in early testicular development | Fig. 13 - Postulated interaction of molecular players involved in early testicular development
Table 1. Genes implicated in sexual development in mammals
2009 BGD Lecture Slide Text
Note that not all slide text shown and text out of context may not make sense to you in this bullet list form.
Internal Genitalia
- Reproductive Tract
External Genitalia
- Development
- Function
- Abnormalities
Background Notes
- Fertilization
- Week 1
- Kidney
- Endocrine
Online References
UNSW Embryology
- Gonad Development http://embryology.med.unsw.edu.au/Notes/urogen.htm
NIH Bookshelf
- Developmental Biology (Gilbert) - Chapter 17 http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.chapter.4101
- Endocrinology (Nussey and Whitehead) - The Gonad http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.972
Textbook References
- Human Embryology (3rd ed.) Larson Chapter 10 pp266-313
- The Developing Human (6th ed.) Moore & Persaud Chapter 13 p303-346
- Before We Are Born (5th ed.) Moore & Persaud Chapter 14 p289-326
- Essentials of Human Embryology, Larson Chapter 10 p173-205
- Human Embryology, Fitzgerald and Fitzgerald Chapter 21-22 p134-152
Genital System Development
3 stages
- Differentiation of gonad (Sex determination)
- Differentiation of internal genital organs
- Differentiation of external genital organs
- 2nd and 3rd stages dependent on endocrine gonad
Long Maturation Timecourse
- Begins in embryo
- Finishes in puberty
Sex Chromosomes
X Chromosome
- 1400+ genes
- 150 million base pairs
- 95% determined
Chromosome Y
- 200+ genes
- 50 million base pairs
- 50% determined
Human Female Differentiation
- Genes such as Wnt-4 and DAX-1
- necessary for initiation of female pathway ovary development
- female not considered a default process
Sry on Gonad
- Sry gene on Y chromosome
- responsible for testis-determining function
- TDF
- expressed in a subset of somatic cells in developing gonad
- induces cells to differentiate into Sertoli cells
Sertoli cells
- produce signals that promote development of male characteristics
- suppress development of female characteristics
- induce primordial germ cells to commit to sperm development
DNA with SRY Protein - SRY protein binds DNA
- Testes determining factor (TDF)
- Transcription factor
Bends DNA 70–80 degrees
- Black
- SRY protein HMG box
- Red coil - DNA double helix (Image after Haqq et al. 1994 and Werner et al. 1995)
SRY on Gonad Development
Germ Cells Development
- Early germ line separation from somatic cells
- germ cells do not arise within gonad
Precursors primordial germ cells (PGCs)
- arise elsewhere and migrate into developing gonads
Gametogenesis
- forming PGCs and getting them into genital ridge as gonad forms
- formation of germ plasm and determination of PGCs
- migration of PGCs into developing gonads
- process of meiosis and modifications of meiosis for forming sperm and eggs
- differentiation of sperm and egg
- hormonal control of gamete maturation and ovulation
Movie: Germ Cell Migration
Sex Determination
Humans (week 5-6)
- Germ cells migrate into gonadal ridge
- Gonads (male/female) identical at this stage
- Indifferent
- Gonad development dependent on sex chromosome
- Y testes
- No Y ovary
Movie: Germ Cell Migration
Primary Sex Cords Carnegie stage 13/14
Internal Genital Organs
All embryos form paired
- Nephric duct
- Mesonephric duct (See kidney development)
- Paramesonephric duct
- Humans 7th week
- Invagination of coelomic epithelium
- Cord grows and terminates on urogenital sinus
Male Gonad (testes) secretes
- Mullerian duct inhibitory factor (MDIF) - Causes regression of paramesonephric duct
- Testosterone - Retains mesonephric duct
Female - opposite
Carnegie stage 13/14 Movie: Mesonephros and Gonad Movie: Urogenital Sinus Male Mesonephric Duct (st22) Movie: Gonad Development Gonad Differentiation Gonadal Cell Types Differentiation of Human Gonads Germ Cells and Ovary Folliculogenesis After colonization of gonad
female germ cells enter prophase of first meiotic division as a mid-gestational hallmark of gender
Perinatally oocytes interact with granulosa cells to form primordial follicles
- cyclic periodicity enter a 3 week growth phase that culminates in meiotic maturation and ovulation
- (study in mouse)
Folliculogenesis Spermatogenesis Inactive until puberty
Seminiferous tubules
- Initially solid (cellular)
- Hollow and active at Puberty
- Cyclic sperm production along length of tubule
Movie: Internal Female Genitalia
Genital Ligaments
Movie: Gonad Descent External Genitalia
Human Sex Hormones
- Hormonal production of differentiated gonads
- required for differentiation of internal and external genitalia during fetal life
- development of secondary sex characteristics at puberty
- Antimullerian hormone (AMH) secreted by Sertoli cells
- Testosterone secreted by Leydig cells
- External male genitalia
- requires transformation of testosterone to dihydrotestosterone
- 5alpha reductase type 2 expressed in genital skin and urogenital sinus
- effects of androgens occur in presence of functional androgen receptor protein
- Mutations of genes coding for steroidogenic enzymes, AMH, AMH receptor, AR and 5alpha reductase are all associated with impairment of sex differentiation and result in genital ambiguity
Hormone Axis
Hormone Dependent Genitalia
External Genital Organs
All embryos initially same (indifferent)
Testosterone
- Differentiates male
Fetal Development
External Genitalia Genital Abnormalities Chromosomal
Hermaphroditism
Gonadal Dysfunction
Tract Abnormalities
External Genitalia
Gonadal Descent
Gonadal Descent Cryptorchadism
- One or both testes fail to descend into scrotum
- 1:30 live male births
- May be associated with other abnormalities
Chromosomal Turner’s Syndrome
- Monosomy XO
- 99% non-viable embryos
- Fail to sexually mature at puberty
Klinefelter's Syndrome
- 47, XXY
- Begin normal male, become infertile
- Tall, mental dullness, behaviour problems
Males
- 46, XX
- Develop as male, infertile adults
- Portion of SRY gene located on one X
Sex Reversal in Humans Hermaphroditism True
- 46,XX
- Gonads both ovary and teste tissues
- Ovotestes or ovary and testes
Male Pseudohermaphrodites
- 46,XY
- Gonads of one sex, external genitalia of opposite
- Various causes
Female Intersex (old term Pseudohermaphrodites)
- 46,XX
- Gonads are ovaries, external genitalia ambiguous
- Hyperplastic adrenals secrete androgens
Gonadal Dysfunction
- Gonads fail to develop properly
Gonadal Dysgenesis
- Swyer’s syndrome
- 46,XX
Mixed Gonadal Dysgenesis
- 45,X/46,XY
Primary Hypogonadism
- Affected females 46,XX
Primary Hypogonadism
- Defective anterior pituitary production of gonadotropin
- Lack of gonadotropin-releasing hormone
Tract Abnormalities
- Many different forms
- Uterine - Associated with other anomolies
- Vagina - Agenesis, atresia (See endocrine lecture DES)
- Ductus Deferens - Uni- or bilateral absence - Failure of mesonephric duct to differentiate
External Genitalia
Multi-factoral
- Chromosomal, single gene, environmental
- Developmental arrest gives ambiguous
Androgen Insensitivity Syndrome
XY karyotype and presence of testes
Externally - develop female secondary sex characteristics
Internally
- women lack Müllerian duct derivatives
- have undescended testes
Summary of Gonad Development
Sex Differences in Adult and Developing Brains
- not known significance of brain sex differences
- transient sex differences in gene expression in developing brains may cause permanent differences in brain structure
- may prevent as well, by compensating for potentially differentiating effects of sex differences in gonadal hormone levels and sex chromosomal gene expression
Sex Chromosomes and Brain Sexual Differentiation
Brains of males and females differ
- in regions specialized for reproduction
- in other regions (controlling cognition, etc) where sex differences are not necessarily expected
Differentially susceptible to neurological and psychiatric disease
2 sources of sexually dimorphic information
- complement of sex chromosome genes
- mix of gonadal hormones
- sex differences in the brain have been attributed to the differential action of gonadal hormones
- evidence for sex chromosome effects on both neural and non-neural systems
- XX and XY cells differentiate even before they are influenced by gonadal hormones
- even if exposed to similar levels of gonadal steroids
Molecular Signaling Cascades
Hormone Axis - Puberty LH & FSH
Factors that increase gonadotrophin secretion and stimulate gonadal maturation
Bars show proportional rise in testosterone and estradiol secretions in males and females respectively
Activation of positive feedback mechanism of estradiol in females also occurs during puberty
Hormone Axis - Reproduction
Human Sexual Differentiation
gonads, internal genital ducts, and external genital structures develop from bipotential embryologic tissues
Male or female phenotype develops through a cascade of processes which initiate with sex determination and follow with sex differentiation
Karyotype (46, XY or 46, XX)
- of embryo (genetic sex) determines whether primordial gonad differentiates into a testis or an ovary respectively (gonadal differentiation)