Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry

Abstract

Asymmetric cell division is important in generating cell diversity from bacteria to mammals. Drosophila melanogaster neuroblasts are a useful model system for investigating asymmetric cell division because they establish distinct apical–basal cortical domains, have an asymmetric mitotic spindle aligned along the apical–basal axis, and divide unequally to produce a large apical neuroblast and a small basal daughter cell (GMC)1,2. Here we show that Discs large (Dlg), Scribble (Scrib) and Lethal giant larvae (Lgl) tumour suppressor proteins regulate multiple aspects of neuroblast asymmetric cell division. Dlg/Scrib/Lgl proteins show apical cortical enrichment at prophase/metaphase, and then have a uniform cortical distribution. Mutants have defects in basal protein targeting, a reduced apical cortical domain and reduced apical spindle size. Defects in apical cell and spindle pole size result in symmetric or inverted neuroblast cell divisions. Inverted divisions correlate with the appearance of abnormally small neuroblasts and large GMCs, showing that neuroblast/GMC identity is more tightly linked to cortical determinants than cell size. We conclude that Dlg/Scrib/Lgl are important in regulating cortical polarity, cell size asymmetry and mitotic spindle asymmetry in Drosophila neuroblasts.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Localization of Dlg/Scrib/Lgl and regulation in larval and embryonic neuroblasts.
Figure 2: Dlg/Scrib/Lgl specifically regulates basal targeting in metaphase neuroblasts.
Figure 4: Pins and Gαi are apically localized in dlg; lgl/+; scrib/+ embryos.
Figure 3: Dlg/Scrib/Lgl regulate cell size and mitotic spindle asymmetry.
Figure 5: The role of cell size and cortical polarity in specifying neuroblast/GMC identity.

Similar content being viewed by others

References

  1. Knoblich, J.A. Asymmetric cell division during animal development. Nature Rev. Mol. Cell Biol. 2, 11–20 (2001).

    Article  CAS  Google Scholar 

  2. 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 

  3. Ohshiro, T., Yagami, T., Zhang, C. & Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408, 593–596 (2000).

    Article  CAS  Google Scholar 

  4. Peng, C.Y., Manning, L., Albertson, R. & Doe, C.Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408, 596–600 (2000).

    Article  CAS  Google Scholar 

  5. Mathew, D. et al. Recruitment of Scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein. Curr. Biol. 12, 531–539 (2002).

    Article  CAS  Google Scholar 

  6. Strand, D. et al. A human homologue of the Drosophila tumour suppressor gene l(2)gl maps to 17p11.2–12 and codes for a cytoskeletal protein that associates with nonmuscle myosin II heavy chain. Oncogene 11, 291–301 (1995).

    CAS  PubMed  Google Scholar 

  7. Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).

    Article  CAS  Google Scholar 

  8. Kraut, R., Chia, W., Jan, L.Y., Jan, Y.N. & Knoblich, J.A. Role of inscuteable in orienting asymmetric cell divisions in Drosophila. Nature 383, 50–55 (1996).

    Article  CAS  Google Scholar 

  9. Schober, M., Schaefer, M. & Knoblich, J.A. Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts. Nature 402, 548–551 (1999).

    Article  CAS  Google Scholar 

  10. Petronczki, M. & Knoblich, J.A. DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nature Cell Biol. 3, 43–49 (2001).

    Article  CAS  Google Scholar 

  11. Wodarz, A., Ramrath, A., Grimm, A. & Knust, E. Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts. J. Cell Biol. 150, 1361–1374 (2000).

    Article  CAS  Google Scholar 

  12. Schaefer, M., Shevchenko, A. & Knoblich, J.A. A protein complex containing Inscuteable and the Gα-binding protein Pins orients asymmetric cell divisions in Drosophila. Curr. Biol. 10, 353–362 (2000).

    Article  CAS  Google Scholar 

  13. 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 

  14. Wodarz, A., Ramrath, A., Kuchinke, U. & Knust, E. Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts. Nature 402, 544–547 (1999).

    Article  CAS  Google Scholar 

  15. Brenman, J.E. et al. Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A. J. Neurosci. 18, 8805–8813 (1998).

    Article  CAS  Google Scholar 

  16. Niethammer, M. et al. CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90. Neuron 20, 693–707 (1998).

    Article  CAS  Google Scholar 

  17. Matsumine, A. et al. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science 272, 1020–1023 (1996).

    Article  CAS  Google Scholar 

  18. Hanada, T., Lin, L., Tibaldi, E.V., Reinherz, E.L. & Chishti, A.H. GAKIN, a novel kinesin-like protein associates with the human homologue of the Drosophila discs large tumor suppressor in T lymphocytes. J. Biol. Chem. 275, 28774–28784 (2000).

    Article  CAS  Google Scholar 

  19. Gomes, J.E. et al. The maternal gene spn-4 encodes a predicted RRM protein required for mitotic spindle orientation and cell fate patterning in early C. elegans embryos. Development 128, 4301–4314 (2001).

    CAS  PubMed  Google Scholar 

  20. Guertin, D.A., Trautmann, S. & McCollum, D. Cytokinesis in eukaryotes. Microbiol. Mol. Biol. Rev. 66, 155–178 (2002).

    Article  CAS  Google Scholar 

  21. Parmentier, M.L. et al. Rapsynoid/partner of inscuteable controls asymmetric division of larval neuroblasts in Drosophila. J. Neurosci. (Online) 20, RC84 (2000).

    Article  CAS  Google Scholar 

  22. Koh, Y.H., Popova, E., Thomas, U., Griffith, L.C. & Budnik, V. Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation. Cell 98, 353–363 (1999).

    Article  CAS  Google Scholar 

  23. Morin, X., Daneman, R., Zavortink, M. & Chia, W. A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila. Proc. Natl Acad. Sci. USA 98, 15050–15055 (2001).

    Article  CAS  Google Scholar 

  24. Bilder, D. & Perrimon, N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403, 676–680 (2000).

    Article  CAS  Google Scholar 

  25. Broadus, J. & Doe, C.Q. Extrinsic cues, intrinsic cues and microfilaments regulate asymmetric protein localization in Drosophila neuroblasts. Curr. Biol. 7, 827–835 (1997).

    Article  CAS  Google Scholar 

  26. Zito, K., Fetter, R.D., Goodman, C.S. & Isacoff, E.Y. Synaptic clustering of Fascilin II and Shaker: essential targeting sequences and role of Dlg. Neuron 19, 1007–1016 (1997).

    Article  CAS  Google Scholar 

  27. Spana, E.P. & Doe, C.Q. The prospero transcription factor is asymmetrically localized to the cell cortex during neuroblast mitosis in Drosophila. Development 121, 3187–3195 (1995).

    CAS  PubMed  Google Scholar 

  28. Vaessin, H. et al. prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila. Cell 67, 941–953 (1991).

    Article  CAS  Google Scholar 

  29. Cai, Y., Chia, W. & Yang, X. A family of snail-related zinc finger proteins regulates two distinct and parallel mechanisms that mediate Drosophila neuroblast asymmetric divisions. EMBO J. 20, 1704–1714 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Bilder for providing scrib1 germ line clones and DNA, B. Chia, V. Budnik, D. St Johnston, H. Vaessin, C. Goodman and M. Kuroda for fly stocks and antibodies, S, Siegrist for Dlg–GFP movies and Fig. 1t, and K. Siller, S. Siegrist, Z. E. Gomes, H.-. Shih, M. Rolls and B. Bowerman for comments. This work was funded by National Institutes of Health grants GM58899, and the Howard Hughes Medical Institute, in which C.Q.D. is an Investigator.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chris Q. Doe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Movie 1

Dlg::GFP shows dynamic apical enrichment adjacent to the apical spindle pole during metaphase in living embryonic neuroblasts. Dlg::GFP and the microtubule-binding protein Zeus::GFP are imaged in a lateral view of a stage 11 embryo. The apical neuroblast cortex is indicated with white arrowheads during mitosis. 180X accelerated. (MOV 2079 kb)

Supplementary Figures

Figure S1 Quantitation of apical/basal cell size ratios in wild type and mutant neuroblasts. (PDF 756 kb)

Figure S3 Quantitation of centrosome and spindle asymmetry in wild type and mutant neuroblasts.

Description of Supplementary Movie 1.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Albertson, R., Doe, C. Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nat Cell Biol 5, 166–170 (2003). https://doi.org/10.1038/ncb922

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb922

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing