Study of asymmetric division in development

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Asymmetric division is a basic mechanism for generating cellular diversity during development, and is often achieved by the asymmetric partition of cell fate determinants into one of two daughter cells. The Drosophila neural stem cells, neuroblasts, have been studied as a model system with which to investigate key aspects of this process, given that neural fate determinants such as Numb and Prospero are segregated into one of the two daughter cells generated by neuroblast division.Two important processes associated with the asymmetric division of neuroblasts are (1) the asymmetric localization of cell fate determinants, which is achieved by specific adapter proteins such as Miranda that themselves localize asymmetrically to the cortex, and (2) the orientation of the mitotic spindle and its coordination with the polarized localization of the determinants, which require the apical Baz-Insc-Pins complex.To understand the cell polarity underlying the asymmetric division of neuroblasts, we have screened for mutations that affect the localization of Miranda, and have revealed a previously unidentified mechanism responsible for the asymmetric localization of all known cell fate determinants during neuroblast division. This mechanism involves a cascade of two cortical tumor suppressor proteins, Lethal (2) giant larvae (Lgl) and Lethal (1) discs large (Dlg), and occurs upstream of the first and independently of the second of these two aspects of asymmetric division. Lgl and Dlg create intrinsic differences between sibling cells by mediating differential cortical protein targeting during mitosis, demonstrating for the first time a link between these tumor suppressor proteins and the asymmetric division of neural stem cells.