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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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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

    • Role of Hoxa-11 in decidualization

    • Novel functional specificity is due to novel transcription factor protein function


Loxodonta africana

What is the difference?

Trichoplax adhaerens


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


Gene ID and Character ID


Characters and character states

FW: wing bladewing bladeelytra

HW: wing bladehalterwing blade


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


Ubx determines character identity, not character state

Ubx -/-, KO

Tomoyasu et al. 2005

Nature, 433:643-647


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


sine oculis

eyeless

eyes absent

dachshund

Example of a ChIN: insect eyes

Jointly necessary and sufficient for eye development in Drosophila.


A) Drosophila:

Toy

{Rx}

so

ey

eya

dach

Optx2

Six 3

Lhx2

B) Xenopus:

ET

Pax6

tll

Rx

{Dach1}

Eya1,2,3


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?


What makes ChINs cohesive?

  • Hypothesis:

    • Transcription factors involved in a ChIN are co-adapted for regulating their target genes.


Enhancesome:

Lots of protein-DNA and protein-protein interactions!


Transcription factors acquire novel regulatory specificity through protein adaptation.

Vinny Lynch


Histological types of placentation

epithelio-chorial P.

endothelio-chorial P.

haemo-chorial P.

Epithelium

Stroma

Maternal blood vessel


Invasive placentation is a derived character of Eutheria

Wildman et al., 2006 PNAS103:3203-


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.


HoxA-11

11 sites = 1.5-2

(background = 0.056)

I= 0.460.18

II= 0.090.05


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


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


Regulation of d-PRL


KN

KN

TF binding-sites in the d-PRL promoter are conserved


Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Hs-Hoxa-11


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


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


Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Opossum-Hoxa-11


Only placental Hoxa-11 can up-regulate d-PRL

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Platypus-Hoxa-11


Only placental Hoxa-11 can up-regulate d-PRL

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Chicken-Hoxa-11


Only placental Hoxa-11 can up-regulate d-PRL

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


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!


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.


Thank you for your attention!


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