title: Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains.
abstract: Asymmetric cell division of Drosophila neural stem cells or neuroblasts is an important process which gives rise to two different daughter cells, one of which is the stem cell itself and the other, a committed or differentiated daughter cell. During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. We identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. It preferentially binds to the aPKC/Bazooka/Partition Defective 6 complex and stabilizes aPKC levels. In clu mutants, Miranda (Mira) and Numb are mislocalized in small percentages of dividing neuroblasts. Adult mutants are short-lived with severe locomotion defects. Clu promotes tumorigenesis caused by loss of function of lethal(2) giant larvae (lgl) in the larval brain. Removal of clu in lgl mutants rescues Mira and Numb mislocalization and restores the enlarged brain size. Western blot analyses indicate that the rescue is due to the down-regulation of aPKC levels in the lgl clu double mutant. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. Our study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore.
authors.forename: Li Hui
authors.initials: LH
authors.lastname: Goh
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.forename: Mei Chin
authors.initials: MC
authors.lastname: Lee
authors.forename: Shuping
authors.initials: S
authors.lastname: Lin
authors.forename: Huashan
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007605:Juvenile Hormones / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000166:cytology / Q000378:metabolism; D008297:Male; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D055495:Neurogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007605:Juvenile Hormones; C107613:Mira protein, Drosophila; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C531978:ab protein, Drosophila; C400774:baz protein, Drosophila; C081435:l(2)gl protein, Drosophila; C060606:numb protein, Drosophila; D044767:Ubiquitin-Protein Ligases; C115015:PKC-3 protein; D011493:Protein Kinase C; C487430:park protein, Drosophila
keywords: Drosophila neuroblast asymmetric division; Parkinson's disease; lgl tumorigenesis suppression