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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. 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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  1. 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

  2. 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.

  3. Background

  4. 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.

  5. Defects in Alignment of the EMS and ABar Spindles. dsh-2(or302) dsh-1(RNAi); dsh-2(or302); mig-5(RNAi)

  6. Defects in EMS

  7. 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.

  8. 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.

  9. 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

  10. dsh-2(RNAi); mig-5(RNAi) wrm-1(RNAi) ABar spindle defects visualized by b-tubulin::GFP TBB-2/ b-tubulin::GFP

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

  12. Discussion Gbg signaling in spindle orientation ?? GSK-3 in spindle orientation ??

  13. 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.

  14. 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.

  15. 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.

  16. Activation of Gbg signaling downstream of Wnt-11/Xfz7 regulates Cdc42 activity. During xenopus gastrulation Penzo-Mendez A et al. Dev Biol, 2003.

  17. 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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