Doe Lab

University of Oregon | Institute of Neuroscience | Institute of Molecular Biology | Howard Hughes Medical Insitute | Eugene, OR

Asymmetric Cell Division

Asymmetric cell division of neural precursors

Drosophila neural precursors (called neuroblasts) repeatedly divide along their apical/basal axis to regenerate an apical neuroblast and bud off a smaller basal daughter cell (called a GMC) that differentiates into a neurons or glia. Normal asymmetric division requires alignment of the mitotic spindle along the apical/basal axis as well as polarized localization of cell fate determinants to the apical or basal poles of the cell -- which allows two molecularly distinct daughter cells to be produced.

We are interested how neuroblasts establish cell polarity, and how cell polarity is used to generate two different cell types at each cell division. Work from our lab and others has identified basally-localized mRNA and proteins (e.g. prospero RNA and Miranda, Prospero, and Numb proteins) as well as apically-localized proteins (e.g. Baz, Par-6, and aPKC). We have done genetic screens to identify new genes involved in apical protein localization, spindle orientation, and basal protein localization, and have identified 12 loci that are required for one or more of these events. A graduate student in the lab, Sarah Siegrist, has developed methods for timelapse imaging of asymmetric neuroblast division both in vivo and in vitro, which is providing new insights into wild type and mutant cell division phenotypes.

Two former graduate students, Chian-Yu Peng and Roger Albertson, have characterized three basal localization mutants, the previously identified "tumor suppressor genes" lethal giant larvae (lgl), discs large (dlg), and scribble. All three mutants show normal apical protein localization and spindle orientation, but a loss of basal protein targeting. Interestingly, these phenotypes can be suppressed by reducing the level of non-muscle myosin II protein, and mimicked by a pan-myosin inhibitor, leading to a model in which both positive and negative myosins regulate basal transport of Miranda and Numb proteins. A third graduate student, Karsten Siller, is working on the role of the dynactin complex and Lis1 in regulating basal protein targeting and spindle orientation in neuroblasts. Karsten has show that Lis1 is essential for normal asymmetric division (both basal targeting and spindle orientation). His results are likely to aid in our understanding of the human Lissencephaly phenotype, which has yet to be characterized at the cellular level. Our work on cell polarity and asymmetric cell division has been supported by HHMI and the NIH.

 

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