Lecture 8—February 23, 2015
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Typical sexual differentiation
background/terms
chromosomes
gonads
hormones
morphology
Wednesday—atypical differentiation
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You can do any test, ask any question, make any observation.
How do you know whether someone is male or female?
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Chromosomes?
Gamete kind or size?
Gonads?
Sex hormone levels?
Phenotype? (i.e., external genitalia,
secondary sex characteristics, brain)
Gender identity?
Behavior?
CAUTION—Sex Determination
Most of the time all these factors align along male and
female lines, but much of the time they don’t
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Terms (just the basics!)
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•Sex=biological sex
– genitalia, gonads, sex chromosomes, hormone levels
•Gender= masculine to feminine
– social, cultural, psychological
•Sexual orientation=pattern of sexual attraction
– to one’s own sex, the opposite sex, or both
•Primary and secondary sex characteristics
– Primary=structures directly involved in reproduction, i.e. gonads and
genitalia
– Secondary=most other sexually dimorphic features, usually emerging at
adolescence, under control of hormones, i.e, facial hair, breasts, muscles,
fat deposits, voice
•Feminization/masculinization=developing, or allowing the possibility
to develop, female traits
•Defeminization/demasculinization=removal of male traits or the
possibility of developing them
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Human sexual differentiation basic timeline
10 weeks
6 weeks
16 weeks
–Sex determination: conception
–Gonads: 5-7 weeks gestation
–Genitalia: 7-17 weeks
–Complete by ~18 weeks
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Sexual determination and differentiation
Just the basics
Scientists are making discoveries and changing
ideas about this process all the time!
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Sexual determination and differentiation
Determination
More info on sex determination and germ cells:
ncbi.nlm.nih.gov/books/NBK26940/
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Sex chromosomes determine sex at fertilization
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Sex chromosomes determine sex at fertilization
•each cell contains 46 chromosomes in pairs (one maternal and one paternal),
23 of each
•22 are autosomes
•23rd pair are the sex chromosomes
•Generally: male, XY; female, XX. Lots of exceptions!
•What are the genetic differences between males and females?
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X and Y sex chromosomes, SRY gene
Much of Y is inactive
(heterochromatic), codes for
50-60 active proteins
Y contains SRY gene,
expressing TDF protein.
TDF is a transcription factor
necessary for male gonadal
differentiation
TDF upregulates other
regulatory genes, (i.e.,
SOX-9) to cause cells in the
gonadal ridge to
differentiate
What if SRY is translocated,
missing, or nonfunctional?
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Barr body
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X inactivation
females have two X
chromosomes in each cell,
males have 1
females would thus have
twice the amount of protein
product from the X as males
to compensate for this, one X
is randomly inactivated in
each cell line of XX females
the inactivated X
chromosome in each cell
nucleus is called a “Barr
body”
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Sexual determination and differentiation
gonad formation is largely
dependent on whether or
not the Y sex chromosome
is present in the embryonic
cells
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Gonadal differentiation basics
0-7 weeks
XX and XY individuals are indistinguishable
Germinal ridge on the surface of the
protokidney is “bipotential;” can become
testes or ovaries, depending on presence of
SRY, TDF, and downstream genes
4-7 weeks
primordial germ cells (PCGs) migrate to the
germinal ridge (4-5 weeks)
In XY, testes begin differentiation (6-7 weeks)
8 weeks
in XY, T first secreted around 8 weeks
SRY gene expression (TDF and downstream
products) directs gonad development prior to
T secretion
pbs.org/wgbh/nova/miracle/determined.html
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Germ cell migration and gonad differentiation
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XY
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gonadal differentiation detail
TDF causes up regulation
of genes causing PGCs to
migrate to medulla -seminiferous tubules,
sertoli and leydig to
develop.
Sertoli cells produce MIH
Leydig cells produce T,
guiding further
masculinization
XX
PGCs migrate to cortex,
ovarian tissue develops
genes such as WNT 4 may
be necessary to suppress
genes related to male
development
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Sexual determination and differentiation
the hormones that are produced
(or not) depend on whether
testes or ovaries are present,
and the hormones direct most of
the rest of sexual differentiation
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Duct differentiation basics
sex chromosomes determine
only how the gonad
differentiates; testes (and T,
MIH) or their absence (and
possibly other genes for XX)
directs the rest of the process
one of two pairs of ducts
develops after gonadal
differentiation, depending on
presence of 2 crucial
testicular products (T and
MIH)
XX=Mullerian ducts - will
develop into fallopian tubes,
uterus, inner vagina (WHY?)
XY=Wolffian ducts - will develop
into epididymis, vas deferens,
and seminal vesicles (WHY?)
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Duct differentiation in XY
In XY--testicular products direct duct
differentiation and stabilization
Sertoli cells produce MIH
between 9-12 weeks, Mullerian duct
cells are most sensitive to MIH
MIH induces Mullerian cell apoptosis
and duct regression
Leydig cells produce T
highest from 11-16 weeks, when
Wolffian duct cells sensitive to T
stabilizes Wolffian ducts (epididymis,
vas deferens, seminal vesicles)
T converted to DHT by 5-alphareductase, masculinizes external
genitalia
Adult
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Duct differentiation in XX
In XX--absence of XY factors allows
female development (pathway not as
well understood as that of the male)
full ovarian function appears to
require expression of specific genes
ovary relatively quiescent until
puberty
no endocrine products required
lack of T causes Wolffian duct to
regress
lack of MIH allows maintenance
of Mullerian duct
Adult
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Sexual determination and differentiation
Androgens from the recently formed
sertoli cells are converted to DHT
in (mostly) external genitalia, leading
to the development of a “male”
external phenotype (i.e., penis,
scrotum) and internal genitalia are
“masculinized” (i.e., vas deferens,
epididymis) by T from the Leydig
cells.
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Roles of T and DHT in differentiation of internal and external male genitalia
DHT masculinizes
external genitalia
penis, scrotum
T masculinizes internal
reproductive structures
Prostate
epididymis
seminal vesicles
vas deferens
What happens if 5-alpha
reductase is not present or
functional, in males, and in
females?
Testosterone- and dihydrotestosterone-dependent regions of the human male
genital system. (After Imperato-McGinley et al. 1974.)
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Differentiation of external genitalia
XY: SRY>TDF >testes>T>DHT
DHT masculinizes external
genitalia
penis develops from genital
tubercle
genital swellings fuse to
become scrotum
testes descend into scrotum
beginning at 12 weeks,
complete before birth
XX: No SRY>no testes>no T or
MIH
clitoris develops from
genital tubercle
genital folds and swelling
become labia minora and
majora
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Timeline of sexual differentiation in humans
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Typical sexual differentiation summary
Presence (or absence) of Y chromosome determines sex
SRY gene on Y chromosome codes for TDF protein, directing sexual
differentiation of bipotential gonad (PGC migration to cortex in XX,
medulla in XY)
The same, dual duct systems (each duct is unipotential) exist in XX and
XY, only one develops depending on gonad differentiation
If testes: Sertoli cells secrete MIH, degrading mullerian ducts; leydig
cells secrete T, stabilizing Wolffian duct
If no testes: Mullerian ducts, female external genitalia, develop in
absence of TDF and MIH
DHT masculinizes external genitalia and prostate; T, duct system
Typical developmental pathways
Male pathway requires X and Y sex chromosomes, SRY gene, TDF, MIH, T, and
appropriate receptors and enzymes. More active process.
Female pathway — two X’s and no Y; other genes possibly involved
Check out:
hopkinschildrens.org/intersex/sd2.html
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