title: The Hippo Pathway Regulates Neuroblasts and Brain Size in Drosophila melanogaster.
abstract: A key question in developmental neurobiology is how neural stem cells regulate their proliferative potential and cellular diversity and thus specify the overall size of the brain. Drosophila melanogaster neural stem cells (neuroblasts) are known to regulate their ability to self-renew by asymmetric cell division and produce different types of neurons and glia through sequential expression of temporal transcription factors [1]. Here, we show that the conserved Hippo pathway, a key regulator of epithelial organ size [2-4], restricts neuroblast proliferative potential and neuronal cell number to regulate brain size. The inhibition of Hippo pathway activity via depletion of the core kinases Tao-1, Hippo, or Warts regulates several key characteristics of neuroblasts during postembryonic neurogenesis. The Hippo pathway is required to maintain timely entry and exit from neurogenesis by regulating both neuroblast reactivation from quiescence and the time at which neuroblasts undergo terminal differentiation. Further, it restricts neuroblast cell-cycle speed, specifies cell size, and alters the proportion of neuron types generated during postembryonic neurogenesis. Collectively, deregulation of Hippo signaling in neuroblasts causes a substantial increase in overall brain size. We show that these effects are mediated via the key downstream transcription co-activator Yorkie and that, indeed, Yorkie overexpression in neuroblasts is sufficient to cause brain overgrowth. These studies reveal a novel mechanism that controls stem cell proliferative potential during postembryonic neurogenesis to regulate brain size.
authors.affiliation: Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Carole L C
authors.initials: CL
authors.lastname: Poon
authors.affiliation: Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Mitchell
authors.affiliation: Laboratory of Invertebrate Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: louise.cheng@petermac.org.
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Cheng
authors.affiliation: Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: kieran.harvey@petermac.org.
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Harvey
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C093503:wts protein, Drosophila; C115483:TAO1 protein kinase; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases