Multiple Wnt Signaling Pathways Converge to Orient
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Multiple Wnt Signaling Pathways Converge to Orient the Mitotic Spindle in Early C. elegans Embryos. Walston T. et al . Developmental Cell , Vol. 7, 831–841, December, 2004. ABpl. Background. The fate of the EMS daughters is controlled by a Wnt/b-cat pathway.

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Multiple Wnt Signaling Pathways Converge to Orient

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Multiple wnt signaling pathways converge to orient

Multiple Wnt Signaling Pathways Converge to Orient

the Mitotic Spindle in Early C. elegans Embryos

Walston T. et al.

Developmental Cell, Vol. 7, 831–841, December, 2004


Multiple wnt signaling pathways converge to orient

ABpl

Background

  • The fate of the EMS daughters is controlled

  • by a Wnt/b-cat pathway.

  • The orientation of the EMS division is

    controlled by a different Wnt pathway involving

    Wnt(MOM-2), Porcupine(Porc;MOM-1),

    Fz(MOM-5), GSK-3(GSK-3b) and CK1a(KIN-19).

  • A pathway involving MES-1, a receptor tyrosine

    kinase, and SRC-1, a Src family tyrosine kinase,

    acts redundantly with Wnt signaling with respect

    to the fate of EMS daughters and the orientation

    of the EMS spindle.

  • mom-1 (Porc), mom-2 (Wnt), mom-5 (Fz), and

    mom-3 (uncloned), cause spindle alignment

    defects in the ABar blastomere of the 8-cell

    embryo.


Multiple wnt signaling pathways converge to orient

Background


Multiple wnt signaling pathways converge to orient

We demonstarate...

  • Although many Wnt signaling components have been identified that participate in spindle orientation, the role of the Dsh family has not been clearly characterized.

  • (dsh-1, dsh-2, mig-5)

  • Loss of function of the CKIhomolog, kin-19, causes defects in the fate of EMS daughter cells. Although the role of CKI in spindle alignment has not been examined, CKIlocalizes to centrosomes and mitotic spindles in vertebrate systems.

  • The nontranscriptional Wnt spindle alignment pathway requires contact from the C blastomereto align the spindle of ABar.

  • Wnt/b-catenin pathway regulates the timing of spindle rotation in ABar,presumably by specifying the fate of neighboring blastomeres.


Multiple wnt signaling pathways converge to orient

Defects in Alignment of the EMS and ABar Spindles.

dsh-2(or302)

dsh-1(RNAi); dsh-2(or302); mig-5(RNAi)


Multiple wnt signaling pathways converge to orient

Defects in EMS


Multiple wnt signaling pathways converge to orient

KIN-19/CKⅠ localizes to centrosomes and DSH-2 accumulates between P2 and EMS.

condensed

chromosome

microtubule

Consistent with P2 signaling to EMS to specify

endoderm fate and EMS spindle orientation.

KIN-19 RNAi → does not affect Dsh-2 localization.


Multiple wnt signaling pathways converge to orient

Fz

APC

Axin

b-cat

NEMO

TCF

RNA pol.

Spindle defects in ABar.

Positive : Dsh, CKⅠ, GSK-3, Src (Dsh background)

Negative : JNK, APC, Axin, b-cat, NEMO, TCF, RNA pol.


Multiple wnt signaling pathways converge to orient

C

Mom-2(Wnt)

Mom-5(Fz)

Mom-5(Fz)

canonical

non-canonical

ABar

EMS

Contact with the C blastomere aligns the spindle in ABar.

Caudal

homolog

laser

killed


Multiple wnt signaling pathways converge to orient

dsh-2(RNAi); mig-5(RNAi)

wrm-1(RNAi)

ABar spindle defects visualized by b-tubulin::GFP

TBB-2/ b-tubulin::GFP


Multiple wnt signaling pathways converge to orient

Three Wnt signaling pathways operate in the Early C. elegans embryos.


Multiple wnt signaling pathways converge to orient

Discussion

Gbg signaling in spindle orientation ??

GSK-3 in spindle orientation ??


Multiple wnt signaling pathways converge to orient

Heterotrimeric G-protein in spindle orientation

D

ABp

ABa

P2

P

A

EMS

V

Gb : GPB-1, GPB-2

Gg : GPC-1, GPC-2

Gotta M et al, Nat Cell Biol, 2001.


Multiple wnt signaling pathways converge to orient

Heterotrimeric G-protein in spindle orientation

C. elegans has 20Ga genes.

→ GOA-1, GPA-16

Conclusion : Gbg signaling, not Ga, participates spindle orientation in C. elegans.

Gotta M et al, Nat Cell Biol, 2001.


Multiple wnt signaling pathways converge to orient

Cdc42 regulates GSK-3b and APC to control cell polarity.

Astrocyte

MTOC : microtubule organizing centre

There is a larger complex containing GSK-3b, Par6, PKCz.

Scratch-induced cell migration assay

: Cdc42, p-GSK-3b, b-cat and APC localize at the leading edge of migrating cell.

Etienne-Manneville S et al. Nature, 2003.


Multiple wnt signaling pathways converge to orient

Activation of Gbg signaling downstream of Wnt-11/Xfz7 regulates Cdc42 activity.

During xenopus gastrulation

Penzo-Mendez A et al. Dev Biol, 2003.


Multiple wnt signaling pathways converge to orient

Canonical Wnt

Non-canonical Wnt

Leading edge

Cdc42, p-GSK-3b

b-cat, APC

Fz

Fz

Mes-1

Gbg

Dvl

Dvl

PKC

Src

Cdc42

RhoA

Par-6

Dvl-1 ?

Dvl-2 ?

Dvl-3 ?

PKCz

GSK-3b

CKⅠ

MEKK, SEK

Axin

APC

b-cat

JNK

Polarity

b-cat

b-cat

b-cat

b-cat

Cell fate,

spindle rotation

Tcf/Lef


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