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Evolution of Gene Regulation in the Endometrium: a mammalian novelty

Evolution of Gene Regulation in the Endometrium: a mammalian novelty. Günter P. Wagner & Vincent Lynch Yale University. Topics. Conceptual: What is a novelty What is a character What is genetic basis of character identity Empirical Evolution of Hox genes in mammals

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Evolution of Gene Regulation in the Endometrium: a mammalian novelty

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  1. Evolution of Gene Regulation in the Endometrium:a mammalian novelty Günter P. Wagner & Vincent Lynch Yale University

  2. Topics • Conceptual: • What is a novelty • What is a character • What is genetic basis of character identity • Empirical • Evolution of Hox genes in mammals • Role of Hoxa-11 in decidualization • Novel functional specificity is due to novel transcription factor protein function

  3. Loxodonta africana What is the difference? Trichoplax adhaerens

  4. What is essential about being a character? • Character is the entity that has historical continuity • Character states are the modifications that body part undergoes in evolution. • Developmental quasi-independence (DQI): • i.e. the ability to execute a developmental program different from that of other parts of the body. • DQI ensures phylogenetic continuity of a character: • i.e. descent with modification

  5. Gene ID and Character ID

  6. Characters and character states FW: wing blade wing blade elytra HW: wing blade halter wing blade

  7. There are genes that determine character identity but NOT character state:

  8. Ubx determines character identity, not character state Ubx -/-, KO Tomoyasu et al. 2005 Nature, 433:643-647

  9. Is there a material basis for Character Identity? • Hypothesis: ChIN (Character Identity Network) Positional Information Signals ChIN Character Identity Network Character Identity “Realizer” Genes Character States

  10. sine oculis eyeless eyes absent dachshund Example of a ChIN: insect eyes Jointly necessary and sufficient for eye development in Drosophila.

  11. A) Drosophila: Toy {Rx} so ey eya dach Optx2 Six 3 Lhx2 B) Xenopus: ET Pax6 tll Rx {Dach1} Eya1,2,3

  12. What is a Novelty? • Evolution of Body Plan Complexity = Evolution of Novel ChIN, novel Characters. • Questions: • How do ChINs arise? • What makes ChINs cohesive and conserved? • How does genome duplication contribute to character innovation? • What is the role of novel miRNAs in the origin of characters?

  13. What makes ChINs cohesive? • Hypothesis: • Transcription factors involved in a ChIN are co-adapted for regulating their target genes.

  14. Enhancesome: Lots of protein-DNA and protein-protein interactions!

  15. Transcription factors acquire novel regulatory specificity through protein adaptation. Vinny Lynch

  16. Histological types of placentation epithelio-chorial P. endothelio-chorial P. haemo-chorial P. Epithelium Stroma Maternal blood vessel

  17. Invasive placentation is a derived character of Eutheria Wildman et al., 2006 PNAS103:3203-

  18. Functions of AbdB related HoxA Genes • In mammals, the expression of HoxA-13, HoxA-11, HoxA-10 and HoxA-9 along the Müllerian duct is essential for the development and function of the female reproductive tract. • These genes continue to be expressed in adults. • HoxA-10 and HoxA-11 are required for endometrial stroma differentiation and hence for implantation.

  19. HoxA-11 11 sites = 1.5-2 (background = 0.056) I= 0.460.18 II= 0.090.05

  20. Hoxa-11 is necessary for endometrial stroma cell differentiation:Hoxa-11 knock down effects

  21. Taylor et al., 1997, 98 Du et al., 2005 Hoxa-10 P4, ES, VDR Yao et al., 2003 Kim et al., 2003 Hoxa-11 This study. PRL Coherent FF network type1

  22. Regulation of d-PRL

  23. KN KN TF binding-sites in the d-PRL promoter are conserved

  24. Reporter experiment in HeLa cells Luciferase MER20 Hs-Foxo1A Hs-Hoxa-11

  25. Placental Hoxa-11 and FOXO1A cooperate in regulating decidual PRL expression.

  26. Evolution of d-PRL expression: d-PRL neg neg (neg/?) (neg/?) pos Amphibians Sauropsids Monotremes Marsupials Is non-placental HoxA11 also able to up-regulate d-PRL? Placentals

  27. Reporter experiment in HeLa cells Luciferase MER20 Hs-Foxo1A Opossum-Hoxa-11

  28. Only placental Hoxa-11 can up-regulate d-PRL HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A

  29. Reporter experiment in HeLa cells Luciferase MER20 Hs-Foxo1A Platypus-Hoxa-11

  30. Only placental Hoxa-11 can up-regulate d-PRL HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A

  31. Reporter experiment in HeLa cells Luciferase MER20 Hs-Foxo1A Chicken-Hoxa-11

  32. Only placental Hoxa-11 can up-regulate d-PRL HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A HoxA11 + HsFOXO1A

  33. Evolution of HoxA11 activity: Hoxa-11 Activity Down Down Down Up Amphibians Sauropsids Monotremes Marsupials Evolution of d-PRL up-regulation by HoxA11 Placentals This new regulatory activity is due to changes in the HoxA11 protein!

  34. Conclusions • Character identity and character states are represented by different genetic elements • Character identity is based on conserved ChIN. • Character states are determined by genes downstream of ChIN • Novelties=new characters=new ChIN. • Transcription factors in ChINs are co-adapted for their specific derived functions • ChINs are unique with respect to Ch-ID.

  35. Thank you for your attention!

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