The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts

Article metrics

Abstract

Drosophila neuroblasts are a model system for studying asymmetric cell division: they divide unequally to produce an apical neuroblast and a basal ganglion mother cell that differ in size, mitotic activity and developmental potential. During neuroblast mitosis, an apical protein complex orients the mitotic spindle and targets determinants of cell fate to the basal cortex1, but the mechanism of each process is unknown. Here we show that the tumour-suppressor genes lethal giant larvae (lgl) and discs large (dlg) regulate basal protein targeting, but not apical complex formation or spindle orientation, in both embryonic and larval neuroblasts. Dlg protein is apically enriched and is required for maintaining cortical localization of Lgl protein. Basal protein targeting requires microfilament and myosin function, yet the lgl phenotype is strongly suppressed by reducing levels of myosin II. We conclude that Dlg and Lgl promote, and myosin II inhibits, actomyosin-dependent basal protein targeting in neuroblasts.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Lgl and Dlg are required for basal protein targeting but not spindle orientation in embryonic neuroblasts.
Figure 2: Lgl and Dlg are required for basal protein targeting in larval brain neuroblasts.
Figure 3: Dlg and Lgl protein localization in neuroblasts.
Figure 4: Myosins negatively and positively regulate basal protein targeting in neuroblasts.

References

  1. 1

    Doe, C. Q. & Bowerman, B. Asymmetric cell division: fly neuroblast meets worm zygote. Curr. Opin. Cell Biol. (in the press).

  2. 2

    Jan, Y. N. & Jan, L. Y. Asymmetry across species. Nature Cell Biol. 1, E42–E44 (1999).

  3. 3

    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).

  4. 4

    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).

  5. 5

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

  6. 6

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

  7. 7

    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).

  8. 8

    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).

  9. 9

    Fujita, Y. et al. Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process. Neuron 20, 905–915 (1998).

  10. 10

    Lehman, K., Rossi, G., Adamo, J. E. & Brennwald, P. Yeast homologues of tomosyn and lethal giant larvae function in exocytosis and are associated with the plasma membrane SNARE, Sec9. J. Cell. Biol. 146, 125–140 (1999).

  11. 11

    Kagami, M., Toh-e, A. & Matsui, Y. Sro7p, a Saccharomyces cerevisiae counterpart of the tumor suppressor l(2)gl protein, is related to myosins in function. Genetics 149, 1717–1727 (1998).

  12. 12

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

  13. 13

    Manfruelli, P., Arquier, N., Hanratty, W. P. & Semeriva, M. The tumor suppressor gene, lethal(2)giant larvae (1(2)g1), is required for cell shape change of epithelial cells during Drosophila development. Development 122, 2283– 2294 (1996).

  14. 14

    Woods, D. F., Hough, C., Peel, D., Callaini, G. & Bryant, P. J. Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia. J. Cell. Biol. 134, 1469–1482 (1996).

  15. 15

    Truman, J. W. & Bate, M. Spatial and temporal patterns of neurogenesis in the central nervous system of Drosophila melanogaster. Dev. Biol. 125, 145–157 (1988).

  16. 16

    Lu, B., Rothenberg, M., Jan, L. Y. & Jan, Y. N. Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors. Cell 95, 225–235 ( 1998).

  17. 17

    Ikeshima-Kataoka, H., Skeath, J. B., Nabeshima, Y., Doe, C. Q. & Matsuzaki, F. Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions. Nature 390, 625–629 ( 1997).

  18. 18

    Shen, C. P., Jan, L. Y. & Jan, Y. N. Miranda is required for the asymmetric localization of Prospero during mitosis in Drosophila. Cell 90, 449–458 (1997).

  19. 19

    Skeath, J. B. & Doe, C. Q. Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates in the Drosophila CNS. Development 125, 1857– 1865 (1998).

  20. 20

    Strand, D. et al. The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain. J. Cell. Biol. 127, 1361– 1373 (1994).

  21. 21

    Hajjar, R. J., Ingwall, J. S. & Gwathmey, J. K. Mechanism of action of 2,3-butanedione monoxime on contracture during metabolic inhibition. Am. J. Physiol. 267, H100–H108 (1994).

  22. 22

    Lu, B., Ackerman, L., Jan, L. Y. & Jan, Y. N. Modes of protein movement that lead to the asymmetric localization of partner of Numb during Drosophila neuroblast division. Mol. Cell. 4, 883–891 (1999).

  23. 23

    Chou, T. B. & Perrimon, N. The autosomal FLP-DFS technique for generating germline mosaics in Drosophila melanogaster. Genetics 144, 1673–1679 (1996).

  24. 24

    Manning, L. & Doe, C. Q. Prospero distinguishes sibling cell fate without asymmetric localization in the Drosophila adult external sense organ lineage. Development 126, 2063 –2071 (1999).

  25. 25

    Stanley, H., Botas, J. & Malhotra, V. The mechanism of Golgi segregation during mitosis is cell type-specific. Proc. Natl Acad. Sci. USA 94, 14467–14470 (1997).

Download references

Acknowledgements

We thank H. Dou for assistance in the deficiency screen; S, Scheider for phylogenetic analysis of Lgl; S. Siegrist and S. Fuerstenberg for Supplementary Fig. 1a–h; D. Bilder, J. K. Roy and N. Perrimon for sharing unpublished results, the FRT lgl4 chromosome, and some lglGLC embryos; B. Mechler, V. Malhotra, B. Chia, E. Knust, M. Peifer, Y. N. Jan, P. Bryant, C. Logan, R. Nusse and the Bloomington stock centre for providing antibodies or fly stocks; and T. Isshiki, S. Fuerstenberg, B. Bowerman for comments and sharing unpublished data. This work was supported by the NIH and HHMI, of which C.Q.D. is an Associate Investigator.

Author information

Correspondence to Chris Q. Doe.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.