Developmental Genetics, Developmental Genetics,

I.I. How do different cell types become organized How do different cell types become organized into tissues, organs & systems?into tissues, organs & systems?

II.II. Sex determination in DrosophilaSex determination in Drosophila

III.III. Sex determination in MammalsSex determination in Mammals

Genetics of developmentGenetics of developmentzygote adultzygote adult

The transformation from a zygote to a The transformation from a zygote to a multicelled organism involves a series multicelled organism involves a series of “genetic switches” that regulate a of “genetic switches” that regulate a cascade of developmental eventscascade of developmental events

Developmental Genetics:Subfield of genetics concerned with the roles genes play in orchestrating the changes that occur during development.

model organisms: fruit fly, nematode, frog, mouse

Differential cell types of the body are Differential cell types of the body are distinguished by the variety and distinguished by the variety and amounts of protein that they expressamounts of protein that they express

Genetic regulatory decisions:Genetic regulatory decisions: what what wherewhere whenwhen how muchhow much

I. How do different cell types become I. How do different cell types become organized into tissues, organs & systems?organized into tissues, organs & systems?

A.A. Developmental pathwayDevelopmental pathway: : Developmental pathways consist of sequences Developmental pathways consist of sequences

of various regulatory stepsof various regulatory steps In development, cells commit to specific fates In development, cells commit to specific fates

and differentially express subsets of genesand differentially express subsets of genes

1.1. DeterminationDetermination

2.2. DifferentiationDifferentiation

B. Major decisions controlled at the B. Major decisions controlled at the gene transcription level:gene transcription level:

→ Separation of the germ lineSeparation of the germ line

→ Establishment of the sexEstablishment of the sex

→ Establishment of positional informationEstablishment of positional information

→ Subdivision of the body into segments Subdivision of the body into segments (anterior-posterior)(anterior-posterior)

→ Subdivision into germ layers (dorsal-Subdivision into germ layers (dorsal-ventral)ventral)

II. Sex Determination in II. Sex Determination in DrosophilaDrosophila

1993 Nobel Prize - Every cell 1993 Nobel Prize - Every cell determines its sex independentlydetermines its sex independently each cell lineage makes sexual each cell lineage makes sexual

decisiondecision Ratio of X chromosomes to Ratio of X chromosomes to

Autosomes is what determines Autosomes is what determines sex, creating a cascade of sex, creating a cascade of differential (differential (alternate) mRNA alternate) mRNA splicingsplicing

If the pre-mRNA is spliced one way = female, if spliced another = male

sex determined by ratio of X chromosomes to autosomes (A)

XY, AA and XO, AA – X:A ratio of 0.5, male

XX AA and XXX AAA – X:A ratio of 1.0, female

SxlSxl gene and downstream genes gene and downstream genes tratra and and dsxdsx determine sexdetermine sex

SxlSxl “off” produces males “off” produces malesSxlSxl “on” produces females “on” produces females

Ratio of X-chromosome transcription factors (NUM) to Ratio of X-chromosome transcription factors (NUM) to autosomal transcription factors (DEM) affect transcription of autosomal transcription factors (DEM) affect transcription of SxlSxl

basic helix-loop-helix transcription factors (bHLH)basic helix-loop-helix transcription factors (bHLH)function as dimersfunction as dimers

SXL protein activates downstream pathway that leads to female development

Maintaining the switch Maintaining the switch

1. Early promotor of 1. Early promotor of SxlSxl is activated early in embryogenesis. is activated early in embryogenesis.2. Later, and for the rest of the life, 2. Later, and for the rest of the life, SxlSxl is transcribed from the late is transcribed from the late

promoterpromoter Late Sxl transcript is longer, and subject to alternative Late Sxl transcript is longer, and subject to alternative

splicingsplicingIn the presence of SXL a feedback loop is set up maintaining In the presence of SXL a feedback loop is set up maintaining SXL activity:SXL activity:

a)a) SXL causes Female-specific splicing of SXL causes Female-specific splicing of tratra that leads to that leads to active TRAactive TRA

b)b) TRA causes female splicing of TRA causes female splicing of dsx…dsx…c)c) DSX inactivates male specific genes leading to female DSX inactivates male specific genes leading to female

developmentdevelopmentIn In absence of SXLabsence of SXL, there is no functional TRA protein, and , there is no functional TRA protein, and dsxdsx is spliced to produce DSX-M transcription factor which is spliced to produce DSX-M transcription factor which represses female-specific genes, leading to male developmentrepresses female-specific genes, leading to male development

Sex determination pathway is constructed so that the activities of several gene products are needed to shunt the animal from the default state into the female developmental pathway

III. Sex determination in mammalsIII. Sex determination in mammals Not independentNot independent for each cell for each cell

SRYSRY region on Y chromosome codes for TDF which determines region on Y chromosome codes for TDF which determines maleness (binds to DNA and regulates genes controlling the maleness (binds to DNA and regulates genes controlling the development of the testis)development of the testis)

endocrine hormonal systemendocrine hormonal system

Sex is determined by the Sex is determined by the presence or absence of the Ypresence or absence of the Y chromosomechromosome

• Primordial germ cells migrate to the genital ridge, presence of Y Primordial germ cells migrate to the genital ridge, presence of Y determines if they will organize into testes…. determines if they will organize into testes….

• Testosterone will be produced, and this hormone binds to Testosterone will be produced, and this hormone binds to androgen receptors which function as transcription factors androgen receptors which function as transcription factors

• In XX individuals, absence of In XX individuals, absence of SRYSRY and subsequent absence of and subsequent absence of testosterone results in default female shunt pathwaytestosterone results in default female shunt pathway

TDF found on the Y chromosome, causes the male pathway to be activated. This encodes a transcription factor SRY…

Transcription Factors

Repressor

Dosage compensation in Humans, different than Drosophila