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Developmental Genetics, I. II. III. How do different cell types become organized into tissues, organs & systems? Sex determination in Drosophila Sex determination in Mammals Genetics of development zygote 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 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 I. How do different cell types become organized into tissues, organs & systems? A. Developmental pathway: 1. 2. Developmental pathways consist of sequences of various regulatory steps In development, cells commit to specific fates and differentially express subsets of genes Determination Differentiation 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 (dorsalventral) 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 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 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 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: a) SXL causes Female-specific splicing of tra that leads to active TRA b) TRA causes female splicing of dsx… c) 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 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 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 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