Coordination of dev' changes

1
Coordination of dev. changes

• must coordinate many dev. events during
  metamorphosis
• e.g. gills shouldnt regress until lungs have
  dev.
• mechanism for coordination gt different levels of
  hormones produce different effects
• threshold concept
• evidence from thyroidectomized tadpoles
• grow in dilute T gt intestines shorten, hindlimbs
  grow
• high T gt tail regresses before hindlimbs appear
• timing depends on competence of tissue to respond

2
Chromosomal Sex

• sex is established at fertilization based on
  genotype of conceptus (XX female XY male)
• conceptus must possess at least one X chromosome
  to survive
• human X chromosome contains at least 100 genes
• genes on X chromosome confer sex-linked traits
• color vision
• blood clotting
• Y chromosome has very few genes
• identified genes on Y chromosome control
  differentiation of the testes
• important gene on Y chromosome SRY gene
  (sex-determining region on the Y chromosome)

3
Sexually indifferent stage

• gonads, ducts and external genitalia of both
  sexes are identical until 7th week
• gonads develop as bulges at back of abdominal
  cavity (5th week)
• genital ridges have outer cortex, inner medulla
• genital ridges have no germ cells
• during 6th week, 2 pairs of accessory ducts
  appear
• Wolffian ducts (mesonephric ducts)
• Mullerian ducts (paramesonephric ducts)
• undifferentiated external genitalia
• genital tubercle (phallus)
• urogenital folds (urethral folds)
• labioscrotal swelling (genital swelling)

4
Primordial germ cells

• originate in yolk sac (extraembryonic membrane)
• present at 3 weeks
• migrate to hindgut and reach region of kidneys 4
  weeks
• expand by mitosis en route (100 start, 1700
  arrive)
• if genotype is male, PGCs migrate into medulla of
  genital ridge
• if female, PGCs enter cortex
• genital ridges produce chemotactic signals for
  PGCs

5
Male differentiation

• male phenotype detectable as PGCs colonize
• medullary cords develop and contact mesonephric
  tissue
• together, tissues form the definitive testis
  cords
• testis cords incorporate PGCs within and secrete
  outer membrane gt seminiferous tubules
• PGCs now know as prospermatogonia
• Sertoli cells present at this time (from
  mesoderm)
• cells surrounding cords become Leydig cells
• testosterone production by Leydig cells causes
  descent into scrotum (months 7-9)

6
Hormonal control of male differentiation

• depends on SRY expression
• expressed in Sertoli cells during testis cord
  formation
• after cords form, T takes over directs
  development
• T maintains Wolffian ducts
• Sertoli cells produce MIS gt Mullerian ducts
  degenerate
• T converted to DHT by external genitalia gt
  masculinization
• if T production fails, male accessory organs will
  not develop external genitalia will develop
  female phenotype (e.g. 5 ?-reductase deficiency)
• give T to females gt develop male accessory organs
  and male external genitalia

7
Female differentiation

• in absence of SRY expression, embryo has
  intrinsic tendency to feminize
• differentiation occurs a few weeks later than in
  the male (12 weeks)
• PGCs concentrate in ingrowths of cortex
• enlarging cortex forms ovary with oogonia
• oogonia undergo intense period of mitosis
  (600,000 eggs by 8 weeks 7 million by 5th month)
• those that survive are surrounded by granulosa
  cells and membrane propria remain as primordial
  follicles
• Mullerian ducts become oviducts, uterus, vagina
• Wolffian ducts degenerate (due to lack of T)
• external genitalia feminize

8
Disorders of sexual development

• INTERSEXUALITY gt ambiguous reproductive systems
• True hermaphrodites
• combination of gonadal tissues present
• probably due to mosaicism
• sometimes, ovary and Mullerian duct develop on
  one side, testis and Wolffian duct on the other
• Pseudohermaphrodites
• some aspect of reproductive phenotype does not
  agree with genotype

9
Male PseudohermaphroditismTesticular
Feminization Syndrome

• due to insensitivity to androgens (testosterone,
  DHT)
• involves mutation in gene that encodes androgen
  receptor
• patients have male chromosomes, normal testes and
  secreteT
• unable to respond to T
• result gt female external genitalia Wolffian
  ducts dont differentiate
• Mullerian ducts will disappear since Sertoli
  cells still secrete MIS

10
Male PseudohermaphroditismGuevodoces

• penis at twelve
• common in remote villages of Dominican Republic
• chromosomal males, but female external genitalia
  at birth
• due to deficiency in enzyme 5 alpha reductase
  (converts testosterone to DHT)
• normal testes present Wolffian ducts
  differentiate
• at puberty, high levels of testosterone override
  deficiency in 5 alpha reductase
• external genitalia is converted to male phenotype
  at puberty
• usually continue life as a male

11
Female Pseudohermaphroditism

• known as ferms
• chromosomal females with ovaries
• external genitalia becomes masculinized
• often due to adrenogenital syndrome (or
  congenital adrenal hyperplasia)
• adrenal glands are unable to make stress hormone
  cortisol gt secrete androgens instead
• causes masculinization of external genitalia
• can also cause early secondary male sex
  characteristics

12
SRY gene

• encodes testis determining factor
• has DNA binding domain (HMG box)
• binds to specific sequence in promoter of sex
  determination genes (e.g. MIS)
• induces bending of DNA
• insert SRY DNA into genome of normal XX mouse
  zygote gt dev. testes, male accessory organs,
  penis
• XX male mouse have no functional sperm (due to
  presence of 2 X chroms.)

13
Autosomal genes and sex determinationSOX9

• putative transcription factor with HMG box
• target of SRY?
• individuals lacking functional copy
• develop syndrome campomelic dysplasia
• 75 of XY patients develop as phenotypic females
  or hermaphrodites
• essential for testis formation
• mice studies
• Sox9 expressed only in male genital ridge
• expressed in same cells as SRY
• SRY expression precedes Sox9 exp.

14
SF1

• steroidogenic factor 1
• probably activated by SRY
• activates genes involved in steroid synthesis
• delete SF1 genes from mice gt no adrenals, gonads,
  pituitaries
• particularly important for testis dev.
• MIS
• steroidogenic enzymes

15
Dax1

• history 2 sisters ided with XY genotype
• Y chrom. normal had duplicated small arm of X
  chromosome
• double dosage gt disruption of testis formation
• region cloned gt Dax1
• member of nuclear hormone receptor family
• expressed in genital ridges of mouse embryo
• interaction with SF1?