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

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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

Evolution of Gene Regulation in the Endometrium:a mammalian novelty

Günter P. Wagner & Vincent Lynch

Yale University


Topics

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


What is the difference

Loxodonta africana

What is the difference?

Trichoplax adhaerens


What is essential about being a character

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

Gene ID and Character ID


Evolution of gene regulation in the endometrium a mammalian novelty

Characters and character states

FW: wing bladewing bladeelytra

HW: wing bladehalterwing blade


There are genes that determine character identity but not character state

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


Ubx determines character identity 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

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


Example of a chin insect eyes

sine oculis

eyeless

eyes absent

dachshund

Example of a ChIN: insect eyes

Jointly necessary and sufficient for eye development in Drosophila.


Evolution of gene regulation in the endometrium a mammalian novelty

A) Drosophila:

Toy

{Rx}

so

ey

eya

dach

Optx2

Six 3

Lhx2

B) Xenopus:

ET

Pax6

tll

Rx

{Dach1}

Eya1,2,3


Evolution of gene regulation in the endometrium a mammalian novelty

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

What makes ChINs cohesive?

  • Hypothesis:

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


Enhancesome

Enhancesome:

Lots of protein-DNA and protein-protein interactions!


Transcription factors acquire novel regulatory specificity through protein adaptation

Transcription factors acquire novel regulatory specificity through protein adaptation.

Vinny Lynch


Histological types of placentation

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

Invasive placentation is a derived character of Eutheria

Wildman et al., 2006 PNAS103:3203-


Functions of abdb related hoxa genes

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.


Evolution of gene regulation in the endometrium a mammalian novelty

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

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


Coherent ff network type1

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

Regulation of d-PRL


Evolution of gene regulation in the endometrium a mammalian novelty

KN

KN

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


Reporter experiment in hela cells

Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Hs-Hoxa-11


Placental hoxa 11 and foxo1a cooperate in regulating decidual prl expression

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


Evolution of d 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 cells1

Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Opossum-Hoxa-11


Only placental hoxa 11 can up regulate d prl

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

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


Reporter experiment in hela cells2

Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Platypus-Hoxa-11


Only placental hoxa 11 can up regulate d prl1

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

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


Reporter experiment in hela cells3

Reporter experiment in HeLa cells

Luciferase

MER20

Hs-Foxo1A

Chicken-Hoxa-11


Only placental hoxa 11 can up regulate d prl2

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

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A

HoxA11

+

HsFOXO1A


Evolution of hoxa11 activity

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

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

Thank you for your attention!


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