Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation.
Regulation of stem cell self-renewal versus differentiation is critical for embryonic development and adult tissue homeostasis. Drosophila larval neuroblasts divide asymmetrically to self-renew, and are a model system for studying stem cell self-renewal. Here we identify three mutations showing increased brain neuroblast numbers that map to the aurora-A gene, which encodes a conserved kinase implicated in human cancer. Clonal analysis and time-lapse imaging in aurora-A mutants show single neuroblasts generate multiple neuroblasts (ectopic self-renewal). This phenotype is due to two independent neuroblast defects: abnormal atypical protein kinase C (aPKC)/Numb cortical polarity and failure to align the mitotic spindle with the cortical polarity axis. numb mutant clones have ectopic neuroblasts, and Numb overexpression partially suppresses aurora-A neuroblast overgrowth (but not spindle misalignment). Conversely, mutations that disrupt spindle alignment but not cortical polarity have increased neuroblasts. We conclude that Aurora-A and Numb are novel inhibitors of neuroblast self-renewal and that spindle orientation regulates neuroblast self-renewal.
Lee
Cheng-Yu
CY
Institutes of Neuroscience and Molecular Biology, Howard Hughes Medical Institute, University of Oregon, Eugene, Oregon 97403, USA.
Andersen
Ryan O
RO
Cabernard
Clemens
C
Manning
Laurina
L
Tran
Khoa D
KD
Lanskey
Marcus J
MJ
Bashirullah
Arash
A
Doe
Chris Q
CQ
D000818:Animals; D064127:Aurora Kinases; D001921:Brain / Q000166:cytology / Q000196:embryology; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D016764:Cell Polarity / Q000502:physiology; D004330:Drosophila / Q000166:cytology* / Q000254:growth & development; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D007605:Juvenile Hormones / Q000502:physiology*; D007814:Larva / Q000033:anatomy & histology / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D008941:Spindle Apparatus / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D007605:Juvenile Hormones; C060606:numb protein, Drosophila; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases