TheDrosophilaLkb1 kinase is required for spindle formation and asymmetric neuroblast division

Abstract

We have isolated lethal mutations in the Drosophila lkb1 gene (dlkb1), the homolog of C. elegans par-4 and human LKB1 (STK11), which is mutated in Peutz-Jeghers syndrome. We show that these mutations disrupt spindle formation, resulting in frequent polyploid cells in larval brains. In addition, dlkb1 mutations affect asymmetric division of larval neuroblasts (NBs); they suppress unequal cytokinesis, abrogate proper localization of Bazooka, Par-6, DaPKC and Miranda, but affect neither Pins/G␣i localization nor spindle rotation. Most aspects of the dlkb1 phenotype are exacerbated in dlkb1 pins double mutants, which exhibit more severe defects than those observed in either single mutant. This suggests that Dlkb1 and Pins act in partially redundant pathways to control the asymmetry of NB divisions. Our results also indicate that Dlkb1 and Pins function in parallel pathways controlling the stability of spindle microtubules. The finding that Dlkb1 mediates both the geometry of stem cell division and chromosome segregation provides novel insight into the mechanisms underlying tumor formation in Peutz-Jeghers patients.

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

“…1G), suggesting the loss of lkb1 function might affect NB asymmetric cell division. Indeed, lkb1 mutations have been reported to elicit multiple defects in NB asymmetric divisions (66). However, this phenotype is mild in comparison with those of other proteins involved in regulating NB asymmetric cell division, such as Lgl, Brat, aPKC, and AurA (67)(68)(69)(70)(71)(72).…”

LKB1; linking cell structure and tumor suppression

“…These results are consistent with the notion that polarity serves to restrain cell proliferation induced by mitogenic stimuli. Another attractive possibility is that the polarity defects accompanying LKB1 inactivation could contribute to tumorigenesis by impairing genomic stability as has been shown in Drosophila (Bonaccorsi et al, 2007;Lee et al, 2007). Large-scale RNAi screens in Drosophila cell lines suggest that Lkb1 and AMPK are required for normal cellular division (Bettencourt-Dias et al, 2004).…”

Elaborating polarity: PAR proteins and the cytoskeleton

“…par-4 function is required during C. elegans oogenesis, prior to the establishment of AP polarity, raising the possibility that PAR-4 is important for earlier events that prepare the zygote for polarization (Morton et al, 1992). The Drosophila PAR-4 homolog Lkb1 regulates apical-basal polarity under normal (Martin and St Johnson, 2003;Bonaccorsi et al, 2007;Amin et al, 2009) and low-energy (Lee et al, 2007;Mirouse et al, 2007) conditions. 'Anterior' and 'posterior' PAR proteins polarize the zygote by signaling to effectors that alter the distribution of developmental determinants and regulate spindle positioning.…”