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Ric-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins

Nature Cell Biology volume 7, pages 1091–1098 (2005)Cite this article

Abstract

Asymmetric division of Drosophila neuroblasts (NBs) and the Caenorhabditis elegans zygote uses polarity cues provided by the Par proteins, as well as heterotrimeric G-protein-signalling that is activated by a receptor-independent mechanism mediated by GoLoco/GPR motif proteins1,2. Another key component of this non-canonical G-protein activation mechanism is a non-receptor guanine nucleotide-exchange factor (GEF) for Gα, RIC-8, which has recently been characterized in C. elegans and in mammals3,4,5,6. We show here that the Drosophila Ric-8 homologue is required for asymmetric division of both NBs and pI cells. Ric-8 is necessary for membrane targeting of Gαi, Pins and Gβ13F, presumably by regulating multiple Gα subunit(s). Ric-8 forms an in vivo complex with Gαi and interacts preferentially with GDP–Gαi, which is consistent with Ric-8 acting as a GEF for Gαi. Comparisons of the phenotypes of Gαi, Ric-8, Gβ13F single and Ric-8;Gβ13F double loss-of-function mutants indicate that, in NBs, Ric-8 positively regulates Gαi activity. In addition, Gβγ acts to restrict Gαi (and GoLoco proteins) to the apical cortex, where Gαi (and Pins) can mediate asymmetric spindle geometry.

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Figure 1: Ric-8 interacts preferentially with GDP–Gαi and complexes with Gαi and Pins.
Figure 2: Ric-8 is required for the asymmetric division of NBs by regulating membrane localization of Gαi and Pins.
Figure 3: Ric-8 is required for the asymmetric division of pI cells and Ric-8 is distributed in the cytosol in both NBs and pI cells.
Figure 4: Ric-8 is required for cortical localization and stability of Gβ13F.
Figure 5: ric-8;Gβ13F double GLC NBs display defects similar to NBs lacking ric-8 or Gαi function.

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References

  1. Wodarz, A. & Huttner, W. B. Asymmetric cell division during neurogenesis in Drosophila and vertebrates. Mech. Dev. 120, 1297–1309 (2003).

    Article  CAS  Google Scholar 

  2. Willard, F. S., Kimple, R. J. & Siderovski, D. P. Return of the GDI: the GoLoco motif in cell division. Annu. Rev. Biochem. 73, 925–951 (2004).

    Article  CAS  Google Scholar 

  3. Colombo, K. et al. Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos. Science 300, 1957–1961 (2003).

    Article  CAS  Google Scholar 

  4. Afshar, K. et al. RIC-8 is required for GPR-1/2-dependent Gα function during asymmetric division of C. elegans embryos. Cell 119, 219–230 (2004).

    Article  CAS  Google Scholar 

  5. Couwenbergs, C., Spilker, A. C. & Gotta, M. Control of embryonic spindle positioning and Gα activity by C. elegans RIC-8. Curr. Biol. 14, 1871–1876 (2004).

    Article  CAS  Google Scholar 

  6. Tall, G. G., Krumins, A. M. & Gilman, A. G. Mammalian Ric-8A (synembryn) is a heterotrimeric Gα protein guanine nucleotide exchange factor. J. Biol. Chem. 278, 8356–8362 (2003).

    Article  CAS  Google Scholar 

  7. Kaltschmidt, J. A., Davidson, C. M., Brown, N. H. & Brand, A. H. Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system. Nature Cell Biol. 2, 7–12 (2000).

    Article  CAS  Google Scholar 

  8. Cai, Y., Yu, F., Lin, S., Chia, W. & Yang, X. Apical complex genes control mitotic spindle geometry and relative size of daughter cells in Drosophila neuroblast and PI asymmetric divisions. Cell 112, 51–62 (2003).

    Article  CAS  Google Scholar 

  9. Fuse, N., Hisata, K., Katzen, A. L. & Matsuzaki, F. Heterotrimeric G proteins regulate daughter cell size asymmetry in Drosophila neuroblast divisions. Curr. Biol. 13, 947–954 (2003).

    Article  CAS  Google Scholar 

  10. Yu, F., Cai, Y., Kaushik, R., Yang, X. & Chia, W. Distinct roles of Gαi and Gβ13F subunits of the heterotrimeric G protein complex in the mediation of Drosophila neuroblast asymmetric divisions. J. Cell Biol. 162, 623–633 (2003).

    Article  CAS  Google Scholar 

  11. Bardin, A. J., Le Borgne, R. & Schweisguth, F. Asymmetric localization and function of cell-fate determinants: a fly's view. Curr. Opin. Neurobiol. 14, 6–14 (2004).

    Article  CAS  Google Scholar 

  12. Cismowski, M. J., Takesono, A., Bernard, M. L., Duzic, E. & Lanier, S. M. Receptor-independent activators of heterotrimeric G-proteins. Life Sci. 68, 2301–2308 (2001).

    Article  CAS  Google Scholar 

  13. Kaltschmidt, J. A. & Brand, A. H. Asymmetric cell division: microtubule dynamics and spindle asymmetry. J. Cell Sci. 115, 2257–2264 (2002).

    CAS  PubMed  Google Scholar 

  14. Knust, E. G protein signaling and asymmetric cell division. Cell 107, 125–128 (2001).

    Article  CAS  Google Scholar 

  15. Doe, C. Q. & Bowerman, B. Asymmetric cell division: fly neuroblast meets worm zygote. Curr. Opin. Cell Biol. 13, 68–75 (2001).

    Article  CAS  Google Scholar 

  16. Jan, Y. N. & Jan, L. Y. Asymmetric cell division in the Drosophila nervous system. Nature Rev. Neurosci. 2, 772–779 (2001).

    Article  CAS  Google Scholar 

  17. Matsuzaki, F. Asymmetric division of Drosophila neural stem cells: a basis for neural diversity. Curr. Opin. Neurobiol. 10, 38–44 (2000).

    Article  CAS  Google Scholar 

  18. Bellaiche, Y. et al. The Partner of Inscuteable/Discs-large complex is required to establish planar polarity during asymmetric cell division in Drosophila. Cell 106, 355–366 (2001).

    Article  CAS  Google Scholar 

  19. Kimple, R. J., Kimple, M. E., Betts, L., Sondek, J. & Siderovski, D. P. Structural determinants for GoLoco-induced inhibition of nucleotide release by Gα subunits. Nature 416, 878–881 (2002).

    Article  CAS  Google Scholar 

  20. Izumi, Y., Ohta, N., Itoh-Furuya, A., Fuse, N. & Matsuzaki, F. Differential functions of G protein and Baz-aPKC signaling pathways in Drosophila neuroblast asymmetric division. J. Cell Biol. 164, 729–738 (2004).

    Article  CAS  Google Scholar 

  21. Gotta, M. & Ahringer, J. Distinct roles for Gα and Gβγ in regulating spindle position and orientation in Caenorhabditis elegans embryos. Nature Cell Biol. 3, 297–300 (2001).

    Article  CAS  Google Scholar 

  22. Srinivasan, D. G., Fisk, R. M., Xu, H. & van den Heuvel, S. A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C. elegans. Genes Dev. 17, 1225–1239 (2003).

    Article  CAS  Google Scholar 

  23. Tsou, M. F., Hayashi, A. & Rose, L. S. LET-99 opposes Gα/GPR signaling to generate asymmetry for spindle positioning in response to PAR and MES-1/SRC-1 signaling. Development 130, 5717–5730 (2003).

    Article  CAS  Google Scholar 

  24. Hess, H. A., Roper, J. C., Grill, S. W. & Koelle, M. R. RGS-7 completes a receptor-independent heterotrimeric G protein cycle to asymmetrically regulate mitotic spindle positioning in C. elegans. Cell 119, 209–218 (2004).

    Article  CAS  Google Scholar 

  25. Schaefer, M., Petronczki, M., Dorner, D., Forte, M. & Knoblich, J. A. Heterotrimeric G proteins direct two modes of asymmetric cell division in the Drosophila nervous system. Cell 107, 183–194 (2001).

    Article  CAS  Google Scholar 

  26. Bellen, H. J. et al. The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167, 761–781 (2004).

    Article  CAS  Google Scholar 

  27. Takida, S. & Wedegaertner, P. B. Heterotrimer formation, together with isoprenylation, is required for plasma membrane targeting of Gβγ. J. Biol. Chem. 278, 17284–17290 (2003).

    Article  CAS  Google Scholar 

  28. Yu, F., Morin, X., Cai, Y., Yang, X. & Chia, W. Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization. Cell 100, 399–409 (2000).

    Article  CAS  Google Scholar 

  29. Gho, M. & Schweisguth, F. Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila. Nature 393, 178–181 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank H. Bellen, C.Q. Doe, D. Glover, Y.N. Jan, D. St Johnston, T. Kaufman, C. Klambt, J.A. Knoblich, E. Knust, F. Matsuzaki, S. Roth, F. Schweisguth, X. Yang, A. Wodarz, Developmental Studies Hybridoma Bank (University of Iowa) and the Bloomington Stock Center for generously providing antibodies and fly stocks. We thank F. S. Willard for discussion and support, and W. Chia thanks Y. Cai for stimulating discussions. This work was supported by Temasek Life Sciences Laboratory, Singapore Millennium Foundation (F. Y.) and Wellcome Trust (W. C.).

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Authors and Affiliations

  1. Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604

    Hongyan Wang, Kian Hong Ng, Hongliang Qian, William Chia & Fengwei Yu

  2. Department of Pharmacology, Lineberger Comprehensive Cancer Center and UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    David P. Siderovski

  3. Department of Biological Sciences, National University of Singapore, Singapore, 117604

    William Chia & Fengwei Yu

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Correspondence to William Chia or Fengwei Yu.

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Wang, H., Ng, K., Qian, H. et al. Ric-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins. Nat Cell Biol 7, 1091–1098 (2005). https://doi.org/10.1038/ncb1317

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