Development of the Reproductive Tract

• Female represents the default state, and male gonads are required to initiate change
• Jost Experiments: male characteristics get imposed on the fetus by the testicular hormones testosterone and AMH (anti-müllerian hormone)
• Absence/inactivity of testosterone + AMH leads to the fetus becoming phenotypically female
• Androgens are required, and experiments that blocked hormonal production in gonadal tissues induced female disease

Central Paradigm for Reproductive Tract Development

• Sexually dimorphic establishment of the reproductive tract needs regression of 1 of 2 primitive ducts and maintenance of the remaining one
• Central paradigm for reproductive tract development happens through the SRY gene (sex-determining region of Y chromosome)
• SRY is a DNA-binding protein that controls the activity of certain genes, which is activated shortly before gonadal determination
• SRY is only in placental mammals and marsupials. Its mutation leads to different disorders in sex determination gene(

Gonadogenesis

• COUP-TFII ablation leads to the retention of the Wolffian duct in the female embryo
• Male reproductive tract elimination in the female embryo gets actively promoted by COUP-TFII
• Identity securing factors RUNX1 and granulose cells are required by supporting cells
• Fibroblast growth factor(FGF)promotes Wollfian duct maintenance
• Female mouse embryos lacking Coup-tfil in the Wolffian duct mesenchyme because intersex that contained both female and male reproductive tracts

Genes

• p-ERK signaling in Wolffian duct epithelium is partly responsible for the retention in androgen-independent processes.
• Activated ERK signaling influences COUP-TFII expression, impacting downstream cellular events
• MD & WD = Mullerian & Wolffian ducts

Gonadal Differentiation

• Primordial germ cells arrest in mitosis. And become spermatogonia stem cell pool
• Mitosis of spermatogonia occurs every day post-puberty
• Sertoli cells support spermatogenesis, and granulosa cells support ovaries & oogenesis.
• Leydig cells make testosterone while theca cells make estrogen & progesterone, which is in contact with the oocyte
• Number of oocytes are defined in women

Ovarian Development

• Germ cells lining inside of seminiferous tubules
• Regionalization of the gonad leads to cords enclosing the germ cells in the cortex & the medulla without cords
• Many oocytes die, but some develop within primary, secondary, and tertiary follicles
• Tertiary structures develop in the following order: primordial, primary, secondary, tertiary

Uterine and External Development

• The uterus develops from Mullerian ducts fusing
• Process depends on homeobox genes
• Bipotential gonad is bipotential tissue.
• The shift of androgen independence to dependency in genitalia

Non-binary Development

• Intersex is a term for individuals born with variations in sex characteristics (chromosomes, gonads, sex hormones, or genitalia)
• Intersexuality is not the same as transgender but is not mutually exclusive
• Anatomy doesn't fit binary female v. male, and they don't have to be just external
• Turner's Syndrome involves a complete or partial missing X chromosome

Syndromes

• Klinefelter syndrome involves a male born with an additional X chromosome and affects 1 in 500-1,000 males
• True Hermaphroditism have both Mullerian & Wolffian duct derivatives (ovaries & testicular tissue) with a variable karyotype
• Assignment is based on anatomical findings
• Pseudohermaphroditism is when phenotype does not match genotype
• Female Pseudohermaphroditism involves masculinization due to high levels of androgens (adrenal cortex) or excess maternal androgens (exposure during fetal development)

Deficiencies

• Male Pseudohermaphroditism involves genetic male with more feminine genitalia
• Congenital Adrenal Hyperplasia (caused by lack of enzymes needed to make cortisol & aldosterone) makes the body make excess androgen
• 5-a-reductase deficiency is the deficiency of an enzyme that converts T to DHT
• Chromosomes & gonadal development:

Uterus Abnormalities

• Unicornuate Uterus involves one of the Mullerian ducts not fusing properly.
• Uterus Didelphys is a failure of the Müllerian ducts to fuse, results in two separate structures with the same cavit Uterus Didelphys is with a double cervix and a vaginal septum, potentially requiring surgical correction
• Arcuate Uterus is generally considered a normal variant
• DES-related Uterus is caused by in utero exposure to diethylstilbestrol (DES), which leads to a T-shaped endometrial cavity

Uterus Clinical Implications

• Unicornuate Uterus has increased miscarriage, preterm labor, and reduced endometrial surface area
• Uterus Didelphys has normal fertility, others experience recurrent miscarriage or preterm labor, which may cause fetal positioning complication
• DES-related Uterus has a high risk of ectopic pregnancy/infertility and is associated with increased clear cell carcinoma risk

Male Abnormalities

• Hypospadia: abnormal positioning of the urethral opening (1 in 250 male births)
• Cryptorchidism: testicle doesn't descend (3 in 100 term births and 30 in 100 preterm births)
• Androgen exposure from PCOS women creates prenatal and transgenerational susceptibility to PC ovary conditions

Sex Determination

• Two types of sex determination: environmental & genetic
• Sex can be determined by chromosome content or sex reversal due to the specific exchange (46XX or 46XY).
• The single gene can be essential for initation of mammalian testisi development

Gonadal Determination

• Primary gonadal determination is when the gonads become determined as either testes or ovaries
• Gonad appears week 4 as gonadal sex determined by the SRY gene in an indifferent or bipotential genital ridge
• Genital ridge develops from embryonic mesoderm, cells are found between week 5-week 6
• Differentiation: week 5 cells from coelomic epithelium migrate inward to form primitive sex cords. Between week 6 primordial germ cells begun migrating to gonad

Gamete Development

• Without BMP4, PGCs fail to form. Without Blimp1, specified cells revert to somatic fate rather than becoming germ cells
• Extraembryonic tissue secrete BMP4, and induces germ cell formation from epiblast. Activates pathways like SMAD, and signals epiblast cells to become PGC
• Blimp1 is activated & responds to BMP4 by repressing somatic fate & helping epiblast cells commit to germ cell lineage
• Genes associated with somatic differentiation get regulated by PGC's back to somatic lineages
• Migration's target side is on indifferent gonad on chemokinet gradient to germ cells- signaling protein at gonad, germ cell that migrate twd 14 e source

Signaling

• SDF-1 (stromal cell-derived factor 1) is the attraction chemokine to migrating cells and the receptor is CXCR4
• PDCs in species are in posterior epiblast (in mammals) or extraembryonic mesoderm and must migrate properly.
• Chemokine Signaling (SDF-1) SDC secreted by the gonadal ridge with CXCR4 receptor that expressed on migrating PGCs

Gonadal Differentiation

• At 6 weeks, the presence of the SRY gene in the indifferent gonad means one set of specific genes will be activated causing the indifferent gonad to be turned to testes
• The absence of the SRY gene allows a different set of genes to be activated so ovary can become the default differentiation
• By week 8 (for male embryos with SRY), the cells of the coelomic epithelium differentiate into steroli cells (make MIS (mullerian inhibiting substance, support spermatogenesis)

Development of Internal Genitalia

• These is the regression of 1 in 2 primitive primitive ducts
• Support the development of the other. Internal Genitalia
• 2 cell; germ and stem will develop from primordial germ cell lineage
• Female embryo at week 10 Inner medullary cords degenerate and new cords form in the cortex PGCs mix with these new sex cords (if not cords degenerates)

Germ Cell Development

• Meiosis and gamete development span fetal and adult life
• In males, germ cells associate with testicular cords and the onset of sperm/meiosis begins at puberty
• In females, germ cells associate with somatic pregranulosa cells to to produce primordial follicles
• Miosis begins during later fetal life, Eggs arrest and resume meiosis at ovulation

Sex (Secondary) Determination

• Determines structures outside the gonad, which eventually lead to the outside world
• Internal Genetalia: Wolfling = male, Mullerian = female.

Testes and Hormones

• The two hormones made by the testes will govern the phenotype. SRY Testes produce both Testosterone as Mullerian Inhibiting substance or Antimullerian hormone (AMH)
• At time germ cells are migration are migration, 2 set duct develop and will eventually lead to the outside world.

Development of External Genetalia

• Both sexes start the same structure which develops along different lines with the influence od Hydrootestostrone
• Absence of DHT will develop along the female lines where genital swellings=labia majora
• Development of internal genitalia from the Sry gen on Y chromome controls MIS in MALE In the absence of any hormones from the gonads. Atypical development from Non-binary, where the term intersex occurs

Gonadal Dysgenesis

• Cases which the Sry gene can differ Gonadal dysgenesis (XX or XY) 46XX gonadal dysgenesis (pure gonadal dysgenesis, XX) Individuals have a typical female 46.XX karyotype But underdeveloped and gonads Are often present with primary Amenorrhoea and the development from the absence. Normal female external genitalia and Mullerian formation which are not working

Androgen Insensitivity

• Androgen Insensitivity A mutation in the X-linked androgen receptor gene (AR)causes male to become phenotype female Testosterone produced. Testes Testes present as but female external genitalia

Chromosomes

Chromosomes and gonadal development Meiosis (sexual reproduction) occurs by forming individuals from two parents It occurs on depends meiosis (reproduction depends mitosis) depending on gamete production These cross-overs (genetic recombination) can contribute to the genetic diversity Totipotent and Pluripotent are in the zygotes that have transition from totipoten through the stage to pluripotenet

Genetic Differentiation

• The zygote contains totipotent and pluripotent cells in different stages of its development
• Cells transition from totipotent to pluripotent during the early stages of embryonic development, when the embryo is comprised of a distinct inner cell mass
• Gonads = Soma (germ calls give rise to male and female gametes) azygote = sona Lecture 5 - Germ Call Development

Male Reproduction

• Male reproductive organs contain spermatozoa in the testis
• Role of germ cell: give rise to new organism through differentiation
• Oocytes under rapid Mitotic divisions without new increases in size and form smaller cells called Blastomeres

Gametogenisis and Regulation

• Morula stage leads to the cells differentiate into an outer layer contributing to placenta (tophoblast) and inner cell mass form embryo
• Epiblast forms amniotic cavity and future embryo while Trophoblast cells invade endometrium, forming the syncytiotrophoblast and cytotrophoblast PDCs originate from the epiblast during early gastrulation

Directed Migration at Primitive Streak

Intially PDCs migrate to the posterior primitive streak the extraembryonic mesoderm of the yolk sac These movement which guided is due to the chemotactic SGNL on PDCs directed twd gonodal ridges Proper migration requires extracellular matrix component of fibronectin and adhesion molecules

Primitive Development

Formation at the Claudal (posterior) end From form from the epiblast by towards the and towards the midlike Enblasts cells migrate by germ layerm and differentiate through into three general layer End term are called cut and other international

Endoctrine Distruptors

Endocrine-disruptive signals are Substances in all environ. Some endocrine disruptors (EDCs) can cause an animal to under or over produce the proper regulatory hormone This can result in Altering behaviors.

Molecular Mech of ED

• Mimic or block hormone actions and levels Epigenetic Alterations. Water contamination with dicofol, DDT industrials. Can cause reduced survival rates in different species Interference with Reproduction. Developmental Malfunctions. Disturbances Immune & Nervous System., such as those created by DES

Des and Atypicality

High incidences of abnormalities in genitals T-shaed uterus: narrow endometrial leads to infertility of preganacy loss Are caused by disruption in normal estrogen signalling DES exposure after the normal genalital formation creates the abnormailties and disrupts those May create ectopic pregnancies

Hormonall Activity

Steroids, produced In the adrenal glands for stress. Inter converted from enzymes , made through modification. Derived from. Environmental Factors. The two major functions is Inter conversation hydroxylations and enzyme clipping These affect stress

Glucorticoids

The two major functions is Inter conversation hydroxylations and enzyme clipping Derived Endogenous- Cholestern from virtually all tissue (HMG COA reducate). Hormones to placenta via DHEA-S, converted to adrenal to estrogen + androgens. Also helps with. Ovaran Ca, IVF Low levels of DHEAS lead to addison's DHEAS

Hormone

Hormones = communication between different organs and tissue Help them respond to changes/ Made from cholesterol (steroid), amino acids (peptides), adrenalinaedreaniline (monomers).

Peptide Interactions

Peptides: can't penetrate membrane and trigger effects without a signal C AMP activation, hormone responses. Fetal hormones and sex

Gonads

The HPT axis regulates a hormone signals coming to the anterior Pitvary HPP axis regulated by posttive or neg feedback from teserome Progesteone neg regulate GH levels

GNRH and HPA Activation

In a pulsitial Tells and Pitcary to release FHS and LH LM stimule test and androgen in makes and those ceus in females This has neg + positive regulation This has regressive and positive reulates FSH and Lh Neg testosterone and Inhibin Pos with estrogen production and estrogen production

Hormonal Cycles

The menstrual cycle has three phases: Follucar , Luteal and Cycle reset phases Positive Feedback with high estrogen stimutes hypothalamus pitary releasing large surge of LH Causes doninanate to release egg oocyte- this surge with trigger olvlatin

The Gonads and Signals

Luteum forms after ruptures of the ovarian Signal released as needed to stop LH hormone levels That the two most are proteroerone Oogonia differecate from primodal germ layers (PDCs) 4-6 weeks later Have about 1-1mill PDCs pre-birth

Germs and Support During Germ

Sertolli. cells support, help to norunsh Ledyd cells the make testes Developing sperm move to the base membrane to aduminal to the Lumen membrane. PDCs from epiblast during early gastrulation. Local induction on the extraembryonic cell with BLIMP(PRDI

Hypothalmic Axis

Posterior germ streaks = specification site which require PDCs and are attracted by stromal

At 6 wk in embryno with Sry present, the will undergo vigorous proliferation of Sertolli cell into gonad. If there will be the for germ cells but not cord cells

Gonodal Development

Each secondary cell division product 2 cells to 4 divisions That spermatoid also needs to become matre by transofmming to be a matute which tightly Sperminogeesis requires Then also, from 2 different From the hypomanus, we also have two different pathways which are used to progesteorone and testerone, these two are also used to transport the different signals.

Explore key stages of spermatogenesis, including genetic recombination and spermiogenesis. Learn about acrosome function during fertilization and the roles of Sertoli and Leydig cells. Understand hormonal influences and cellular transformations in sperm development.