Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts.
The choice of self-renewal versus differentiation is a fundamental issue in stem cell and cancer biology. Neural progenitors of the Drosophila post-embryonic brain, larval neuroblasts (NBs), divide asymmetrically in a stem cell-like fashion to generate a self-renewing NB and a Ganglion Mother Cell (GMC), which divides terminally to produce two differentiating neuronal/glial daughters. Here we show that Aurora-A (AurA) acts as a tumor suppressor by suppressing NB self-renewal and promoting neuronal differentiation. In aurA loss-of-function mutants, supernumerary NBs are produced at the expense of neurons. AurA suppresses tumor formation by asymmetrically localizing atypical protein kinase C (aPKC), an NB proliferation factor. Numb, which also acts as a tumor suppressor in larval brains, is a major downstream target of AurA and aPKC. Notch activity is up-regulated in aurA and numb larval brains, and Notch signaling is necessary and sufficient to promote NB self-renewal and suppress differentiation in larval brains. Our data suggest that AurA, aPKC, Numb, and Notch function in a pathway that involved a series of negative genetic interactions. We have identified a novel mechanism for controlling the balance between self-renewal and neuronal differentiation during the asymmetric division of Drosophila larval NBs.
Wang
Hongyan
H
Temasek Life Sciences Laboratory and Department of Biological Sciences, National University of Singapore, Singapore 117604. wanghy@tll.org.sg
Somers
Gregory W
GW
Bashirullah
Arash
A
Heberlein
Ulrike
U
Yu
Fengwei
F
Chia
William
W
D000818:Animals; D064127:Aurora Kinases; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation; D018385:Centrosome / Q000737:chemistry; D004330:Drosophila / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D029721:Drosophila Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology; D007605:Juvenile Hormones / Q000032:analysis / Q000737:chemistry; D007814:Larva / Q000033:anatomy & histology / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology; D008941:Spindle Apparatus / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D029721:Drosophila Proteins; D007605:Juvenile Hormones; C497759:N protein, Drosophila; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; C060606:numb protein, Drosophila; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases