2 - Sexual Differentiation Flashcards
Objectives: Describe the process of gonadal differentiation in the embry and the mechanisms that regulate this process
Objectives: Describe genital duct differentiation in the embry and the mechanisms that regulate this process
Objectives: Describe the differentiation of the urogenital sinus and external genitalia in the embry and the mechanisms that regulate these processes
Objectives: Compare the timing of events associated with sexual differentiation in males and females
Objectives: Explain the underlying events that lead to specific disorders of sexual development
What is the beginning of sexual differentiation?
How is this decided?
Sex determination begins with commitment of indifferent gonads to become testes or ovaries.
The process is genetically programmed.
What is the significance of the Y-Chromosome in sexual determination?
What type of activation pathway does it use?
Y-Chromosome carries SRY (Sex-determining Region on Y-Chromosome) that is essential for inducing the differentio of gonad into testis
SRY gene encodes for a DNA-binding protein that functions as a transcription factor = initiates males testis differentiation; and activation of male specific genes
What are pseudoautosomal regions?
Regions of Y-Chromosome distal ends; location of the SRY Gene on the Short arm of the Y-Chromosome
In females (XX), how is the additional genetic material accounted for? (Dosage Compensation)
Is this uniform through cellular lines?
One of the X-chromosome is inactivated
Inactivated X-chromosome will condense into Barr Body (max = X-chromosomes - 1)
Inactivated in random, thus in ~ half of cells, paternal derived X’s will be inactivated, and in other half, maternal derived X’s will be inactivated
Genes in pseudoautosomal region of inactivated X escape inactivation
Where does the genital ridge form?
What are finger-like projections which grow from the epithelium of the genital ridge into the underlying mesenchyme?
What is the composition of an indefferent gonad?
Ventromedial surface of mesonephros
Primitive Sex Cords
External Cortex + Internal Medulla
What are Primordial Germ Cells (PGCs)?
Where do they originate?
What occurs during migration?
Cells which originate outside of gonad; observed in yolk sac endoderm prior to migration (~ wk 5)
Migrate from yolk sac endoderm to indifferent gonad
During migration, PGCs proliferate and undergo extensive genetic reprogramming; finally colonizing genital ridge
Once PGCs colonize the genital ridge; what occurs?
What determines the type of gonad the genital ridge cells will become?
They are rapidly surrounded by Cords of Somatic Cells
PCGs continue to proliferate; and eventually commit to differentiate becoming Gonocytes (testis) or Oogonia (ovary)
- - -
*It is the sex chromosomes present in somatic cells of the genital ridge that will determine the type of gonad the genital ridge will become
During testis differentiation, what is the effect of the SRY gene w/in somatic cells?
What is SOX9?
Induces these cells to differentiate into Sertoli Cells
SOX9 is a gene which is upregulated by SRY; principle regulator of Sertoli Cell differentiation
What separation prevents the surface epithelium from playing a continued role in testis formation?
What is the first discernable event of testis differentiation?
What forms testis cords?
The separation of the testis cords from the genital ridge by the tunica albuginea
The first histological event of testis differentiation is the appearance of Sertolic Cells
Aggregation of Sertolic Cells around the PGCs forms the testis cords.
What occurs to PGCs within the testis cords?
What have most gonocytes differentated to at this point?
What occurs after birth?
What occurs at puberty?
PGCs transition to gonocytes and enter mitotic arrest
Most gonocytes will have differentiated into prespermatogonia
After birth, they will resume proliferation; however they are prevented from entering meiosis until puberty
What are the precursors for seminiferous tubules?
What changes do they undergo w/puberty?
Testis Cords; remain solid structures until puberty which they develop a lumen (canalize) and become fully functional seminiferous tubules
What can Sertoli Cells release and what is the effect?
Sertoli Cells release paracrine factors that recuit mesenchymal cells to the developing testis
Mesenchymal Cells can differentiation into:
Peritubular Myoid Cells
Enothelial Cells (male-specific vascular)
Leydig Cells (Testosterone, INSL3)
Are germ cells required for seminiferous tubule development?
No, seminiferous tubules can form in absence of germ cells
Clinical: Klinefelter Syndrome
Symptoms
Cause/Karyotype
- With multiple X chromosomes, SRY gene still able to induce testicular differentiation; however the process will be altered
- Adult male w/multiple X’s will have small, firm testes with hyalinized seminiferous tubules and germ cell degeneration
- Cause: Meiotic Nondisjunction; 47, XXY karyotype
What are the three requirements for the differentiation of an ovary?
- Invasion of the cortex by primordial germ cells (Invasion)
- Reactivation of the inactivated X-chromosome in the germ cells (Reactivation)
- Absence of SRY Gene (No SRY)
Clinical: Turner Syndrome
- 45, X karyotype
- May lead to Ovarian dysgenesis due to single X-chromosome
What is the end result of PGCs which migrat to the presumptive ovary?
What occurs to a portion of these cell about the 11th week?
What occurs to those cells?
Proliferate rapidly and differentiate into oogonia, resulting in formation of large pool of oogonia
@ 11th Week, some oogonia will leave the pool of proliferating cells and enter into meiosis, becoming primary oocytes
These cells are arrested in prophase of Meiosis I
Upon the onset of oogonial meiosis, what occurs to other oogonia?
What will aggregate to form a single layer of cells around the primary oocyte?
Atresia (programmed cell death)
Primordial Follices arise as pregranulose cells aggregate to form sigle layer of cells around primary oocytes
What is the fate of the Medullary Cords, Cortical Cords, and Tunical Albuginea in Testis and Ovaries?
- Testis
- Medullary Cords Develop
- No Cortical Cords
- Thick Tunica Albuginea
- Ovary
- Medually Cords Degenerate
- Cortical Cords Develop; break into distinct cell clusers
- No Tunical Albuginea
How do PGCs interact with Cortial Cords?
What occurs ~ month 3 of gestation?
What are primordial follicles?
As Cortical Cords extends from the surface of the epitheliam into the undrlying mesenchyme; PGCs are incorporated into the cortial cords as these cords increase in size
Cortical cords begin to break into primordial follicles (distinct cell clusters)
Primordial Follicles consist of a primary oocytes surrounded by single layer of granulosa cells; each primordial follicle is surrounded by a basal lamina
What is the SRY equivalent in XX cells; and what gene pathway does it promote?
RSPO1 regulates differentiation at genital ridge in XX embryo
Activates WNT4/B-catenin pathway
What does the undifferentiated reproductive tract in males and females consist of prior to week 8?
Where do these empty?
Two sets of genital ducts:
- Mesonephric (Wolffian) Ducts
- Paramesonephric (Müllerian Ducts)
Both empty to the urogenital sinus
If Wolffian (mesonephric) Ducts persist, what will they differentiate to?
- Epididymis
- Ductus Deferens
- Seminal Vesicles
- Ejaculatory Duct
What do Müllerian ducts form?
If they persist, what do they form?
Cadual end fuse to form uterovaginal primordium
Differentiate to:
- Fallopian Tubes
- Uterus
- Cervix
- Upper 1/3 of Vagina
In the male internal geneital structures, what is the role of Testosteron and AMH (in relation to ducts)?
How is the female internal genitalia structure regulated?
- Male Internal Genital Structures
- Testosterone promotes differentiation of Wolffian Ducts
- AMH (Anti Müllerian Hormone) promotes regression of Müllerian Ducts
- In absence of hormone stimulation, female internal genital structures:
- Wolffian Ducts regress
- Müllerian Ducts develop into female internal reproductive tract
Where is AMH released from? What is it’s role?
Where is testosterone released from? What is it’s role and what promotes it?
AMH is released by Sertoli Cells of the fetal testes; induces apoptosis of the Müllerian Ducts
Testosterone is released by fetal Leydig Cells; induces Wolffian Duct differentiation.
Chorionic Gonadotropin (hCG) stimulates testosteroe production by the fetal testes.
What is the most frequent occuring uterine anomalies a result of?
Fusion of the Mullerian Ducts to varying degrees
Clinical: Syndrome of Persistent Mullerian Ducts
Failure of AMH synthesis or failure of AMH-receptor
Mullerian Duct Derivatives are present in inguinal hernias, and the testes often fail to descend and are underdeveloped
What is the role of DHT in external genitalia differentiation? What enzyme permits generation of this substance?
What occurs in the absence of androgen stimulation?
What is hypospadias?
Males require Dihydrotestosterone (DHT), androgen derived from testosterone by action of enzyme 5a-reductase; required for development of male external genitalia and prostate
In the absence of androgen stimulation, primordial external genital structure have inherent tendency to develop into female genitalia
Hypospadias - Micropenis with urethral opening located on ventral surface
What does genital tubercle give rise to?
What does the labioscrotal swelling give rise to?
What does the urethral folds give rise to?
Genital Tubercle - Clitoris / Penis
Labioscrotal Swelling - Labia Majora / Scrotum
Urethral Folds - Form ventral folds of penis / labia minora
Urogenital Sinus differentiation:
Where do prostatic buds develop?
How do the female sex hormones effext differentiation of the urogenital sinus and external genitalia?
M - Prostatic buds develop from urogenital sinus
F - Lower part of vagina forms from walls of urogenital sinus
Female hormons do not effect the differentiation of the urogenital sinus and external genitalia
Clinical: Syndrome of Complete Androgen Resistance in 46, XY embryo
Testes capable of secreting androgens will be present in the abdominal cavity
Both male / female internal genital tracts absent
External Genitalia / Secondary sexual characteristics female
Pubic hair scant or absent
Testes in abdomen, no internal tracts, Vagina, Bald pubic area
Clinical: 5a-Reductase Deficiency in 46, XY embryo
Internal Genitalia - Male
External genitalia - Ambiguous
May be mistaken for female at birth; genitalia will mature as male at puberty
What are the consequences of a 46, XX embryo being exposed to excessive androgens in utero?
Induce varying degrees of virilization of external genitalia
Principle clinical manifestation after 12 weeks of gestation is clitoral hypertrophy
What is the final step of sexual differentiation in males?
What hormones are produced by Leydig Cells and play a role promoting this final step?
Is there variation to this final step? What if it doesn’t happen?
Descent of the testes
- Insulin-LikePeptide 3 (INSL3) - Transabdominal phase of testicular descent
- Testosterone - promotes movement of testes through inguinal canal
Usually occurs between wk 25-32; however can also occur in 1st year of life; if they fail to descend = cryptorchidism
