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Sex Determination in Drosophila What is the Role of Sex Chromosomes in Drosophila? • Humans: XX = female; XY = male • Flies: XX = female; XY = male • Humans: XXY = male; XO = female • Flies: XXY = female; XO = male • The number of X chromosomes is important? – Absolute or relative to the number of autosome sets (two)? X:Autosome Ratio is Critical • XX = female; XY = male • XXY = female; XO = male • RULE: – 2X : 2A --> female – 1X : 2A --> male How to Measure the X:A Ratio? • Numerator proteins are encoded by X – Sis-a, sis-b, sis-c, runt, dpn • Denominator proteins encoded by autosomes – Da, her, emc, gro • Numerator proteins are transcription factors • Denominator proteins block numerators, probably by forming inactive dimers Several Mutations Affect Drosophila Sex Determination XX • • • • XY sex-lethal (Sxl) male (dead) male transformer (tra) male male transformer 2 (tra2) male male doublesex (dsx) intersex intersex Sxl • Master regulatory protein that controls all aspects of sexual development • X:A ratio controls Sxl transcription – Brief window: early promoter What Does Sxl Do? • Sxl = RNA-binding protein – Binds pre-mRNAs: sxl, tra, dsx – Causes “female-specific” mode of splicing Sex-specific RNA Splicing Cascade Sex-specific RNA Splicing Cascade Sex-specific RNA Splicing Cascade Doublesex is Needed for Both Sexes XX • • • • XY Sex-lethal (Sxl) male(dead) male transformer (tra) male male transformer 2 (tra2) male male doublesex (dsx) intersex intersex Regulation of Somatic Sex in Drosophila • Female Male Summary Drosophila • Calculation of X/A • Importance of splicing controls • Cascade of interactions C. elegans Worm Choice • Somatic sex differentiation Hermaphrodite – hermaphrodite or male body? Male Initial Trigger is X:A ratio Chromosomes Autosomes X:A ratio Sex XX 2 2/2 (1) herm X 2 1/2 (0.5) male XX XXX 3 4 2/3 (0.67) male 3/4 (0.75) herm Reading of X:A Ratio is Similar to Fly • Numerator proteins = X-linked genes – fox-1 and sex-1 and others – Prevent expression of master regulatory gene: xol-1 • Denominator proteins (autosome-linked) still unknown What Are Key Downstream Genes? XX • • • • her-1, tra-2 fem-1, 2, 3 tra-1 XO Tra-1 is Critical • • • • Last gene is tra-1 If Tra-1 active herm If not male All others regulate Genetic Analysis • Tra-1 mutations suppress her-1 mutations – Why? • Her-1 is upstream • Her-1 is on in males her-1 --| tra-2 --| fem-1,2,3 --| tra-1 herm --| male Problems • Herm needs to execute two programs after gonad is made – Make sperm – Make eggs Tra-2 Repression Needed for Sperm Production Tra-2 mRNA translation needs to be repressed in germ line cells to get sperm • 3’ region binds inhibitor of translation – If delete 3’ region - herm -> female – Escapes repression, no sperm production • Translational repression of tra-2 by laf-1 • Laf-1 opposed by tra-3 in hermaphrodites – Laf-1 expressed in embryo to allow construction of ovary and again past L3 after sperm are made to allow egg production Fem-3 Also Needed for Sperm • Fem-3 needed for male somatic cells and germ line differentiation – But need to turn off to make eggs • Fem-3 transcription inhibited by tra-2 – But leftover fem-3 mRNAs from spermatogenesis need to be inhibited – by binding of inhibitors (nanos, pumilio, FBF) to 3’ region to turn off protein synthesis during egg formation in herm (L3) after sperm are produced C. elegans Summary • • • • Calculation of X/A Importance of translational controls Cascade of interactions Problem in hermaphrodite of forming both sperm and egg as opposed to just the sperm forming program