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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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slide1

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

slide2

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.

slide4

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.
slide5

Defects in Alignment of the EMS and ABar Spindles.

dsh-2(or302)

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

slide7

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.

slide8

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.

slide9

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

slide10

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

wrm-1(RNAi)

ABar spindle defects visualized by b-tubulin::GFP

TBB-2/ b-tubulin::GFP

slide12

Discussion

Gbg signaling in spindle orientation ??

GSK-3 in spindle orientation ??

slide13

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.

slide14

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.

slide15

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.

slide16

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

During xenopus gastrulation

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

slide17

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