Abstract
Asymmetric division generates cellular diversity by producing daughter cells with different fates. In animals, the mitotic spindle aligns with Par complex polarized fate determinants, ensuring that fate determinant cortical domains are bisected by the cleavage furrow. Here, we investigate the mechanisms that couple spindle orientation to polarity during asymmetric cell division of Drosophila neuroblasts. We find that the tumor suppressor Discs large (Dlg) links the Par complex component atypical Protein Kinase C (aPKC) to the essential spindle orientation factor GukHolder (GukH). Dlg is autoinhibited by an intramolecular interaction between its SH3 and GK domains, preventing Dlg interaction with GukH at cortical sites lacking aPKC. When co-localized with aPKC, Dlg is phosphorylated in its SH3 domain which disrupts autoinhibition and allows GukH recruitment by the GK domain. Our work establishes a molecular connection between the polarity and spindle orientation machineries during asymmetric cell division.
Highlights
Animals are unique in their degree of multicellular organization, with diverse cell types structured into complex tissues and organs
We have identified a mechanism that links the polarity kinase atypical Protein Kinase C (aPKC) to an essential spindle orientation factor, GukH via the tumor suppressor Discs large (Dlg)
In previous work (Newman and Prehoda, 2009), we found that autoinhibition of Dlg is required for spindle orientation during neuroblast asymmetric cell division, but the precise role of autoinhibition has been unclear
Summary
Animals are unique in their degree of multicellular organization, with diverse cell types structured into complex tissues and organs. Asymmetric division is a common mechanism for generating cellular diversity, as it produces daughter cells that assume distinct fates (Knoblich, 2010; Roubinet and Cabernard, 2014). A critical aspect of the molecular mechanism underlying this process is the segregation of unique fate determinants into the resulting daughter cells. As the asymmetrically dividing cell proceeds through mitosis, unique sets of fate determinants become polarized into discrete cortical domains that are bisected by the cleavage furrow as mitosis is completed (Gonczy, 2008; Nance and Zallen, 2011). A key step in asymmetric cell division is the coordination of the polarity axis with the processes that position the cleavage furrow. We use an induced polarity cultured cell system and Drosophila neuroblasts to uncover a mechanism for linking polarity and spindle position during asymmetric cell division
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