Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation
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Lee, Cheng-Yu
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机构:Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
Lee, Cheng-Yu
Andersen, Ryan O.
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机构:Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
Andersen, Ryan O.
Cabernard, Clemens
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机构:Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
Cabernard, Clemens
Manning, Laurina
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机构:Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
Manning, Laurina
Tran, Khoa D.
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Tran, Khoa D.
Lanskey, Marcus J.
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Lanskey, Marcus J.
Bashirullah, Arash
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Bashirullah, Arash
Doe, Chris Q.
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Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USAUniv Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
Doe, Chris Q.
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机构:
[1] Univ Oregon, Howard Hughes Med Inst, Inst Neurosci & Mol Biol, Eugene, OR 97403 USA
[2] Univ Utah, Sch Med, Howard Hughes Med Inst, Dept Human Genet, Salt Lake City, UT 84112 USA
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.