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Developmental Genetics,

Developmental Genetics,. How do different cell types become organized into tissues, organs & systems? Sex determination in Drosophila Sex determination in Mammals. Genetics of development zygote adult.

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Developmental Genetics,

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  1. Developmental Genetics, • How do different cell types become organized into tissues, organs & systems? • Sex determination in Drosophila • Sex determination in Mammals

  2. Genetics of developmentzygote adult The transformation from a zygote to a multicelled organism involves a series of “genetic switches” that regulate a cascade 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

  3. Differential cell types of the body are distinguished by the variety and amounts of protein that they express Genetic regulatory decisions: what where when how much

  4. I. How do different cell types become organized into tissues, organs & systems? • Developmental pathway: • Developmental pathways consist of sequences of various regulatory steps • In development, cells commit to specific fates and differentially express subsets of genes • Determination • Differentiation

  5. B. Major decisions controlled at the gene transcription level: • Separation of the germ line • Establishment of the sex • Establishment of positional information • Subdivision of the body into segments (anterior-posterior) • Subdivision into germ layers (dorsal-ventral)

  6. II. Sex Determination in Drosophila • 1993 Nobel Prize - Every cell determines its sex independently • each cell lineage makes sexual decision • Ratio of X chromosomes to Autosomes is what determines sex, creating a cascade of differential (alternate) mRNA splicing • If the pre-mRNA is spliced one way = female, if spliced another = male

  7. 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

  8. Sxl gene and downstream genes tra and dsx determine sex Sxl “off” produces males Sxl “on” produces females • Ratio of X-chromosome transcription factors (NUM) to autosomal transcription factors (DEM) affect transcription of Sxl • basic helix-loop-helix transcription factors (bHLH) • function as dimers SXL protein activates downstream pathway that leads to female development

  9. Maintaining the switch 1. Early promotor of Sxl is activated early in embryogenesis. 2. Later, and for the rest of the life, Sxl is transcribed from the late promoter • Late Sxl transcript is longer, and subject to alternative splicing • In the presence of SXL a feedback loop is set up maintaining SXL activity: • SXL causes Female-specific splicing of tra that leads to active TRA • TRA causes female splicing of dsx… • DSX inactivates male specific genes leading to female development • In absence of SXL, there is no functional TRA protein, and dsx is spliced to produce DSX-M transcription factor which represses female-specific genes, leading to male development

  10. 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

  11. III. Sex determination in mammals • Not independent for each cell • SRY region on Y chromosome codes for TDF which determines maleness (binds to DNA and regulates genes controlling the development of the testis) • endocrine hormonal system • Sex is determined by the presence or absence of the Y chromosome • Primordial germ cells migrate to the genital ridge, presence of Y determines if they will organize into testes…. • Testosterone will be produced, and this hormone binds to androgen receptors which function as transcription factors • In XX individuals, absence of SRY and subsequent absence of testosterone results in default female shunt pathway

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

  13. Transcription Factors Repressor

  14. Dosage compensation in Humans, different than Drosophila

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