title: Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice.
abstract: Alterations in genes that regulate brain size may contribute to both microcephaly and brain tumor formation. Here, we report that Aspm, a gene that is mutated in familial microcephaly, regulates postnatal neurogenesis in the cerebellum and supports the growth of medulloblastoma, the most common malignant pediatric brain tumor. Cerebellar granule neuron progenitors (CGNPs) express Aspm when maintained in a proliferative state by sonic hedgehog (Shh) signaling, and Aspm is expressed in Shh-driven medulloblastoma in mice. Genetic deletion of Aspm reduces cerebellar growth, while paradoxically increasing the mitotic rate of CGNPs. Aspm-deficient CGNPs show impaired mitotic progression, altered patterns of division orientation and differentiation, and increased DNA damage, which causes progenitor attrition through apoptosis. Deletion of Aspm in mice with Smo-induced medulloblastoma reduces tumor growth and increases DNA damage. Co-deletion of Aspm and either of the apoptosis regulators Bax or Trp53 (also known as p53) rescues the survival of neural progenitors and reduces the growth restriction imposed by Aspm deletion. Our data show that Aspm functions to regulate mitosis and to mitigate DNA damage during CGNP cell division, causes microcephaly through progenitor apoptosis when mutated, and sustains tumor growth in medulloblastoma.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA scott_williams@med.unc.edu gershont@neurology.unc.edu.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Williams
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Crowther
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Hedi
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Lough
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Neill
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Veleta
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Oyarzabal
authors.affiliation: Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Merrill
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Yen-Yu Ian
authors.initials: YY
authors.lastname: Shih
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA scott_williams@med.unc.edu gershont@neurology.unc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002528:Cerebellar Neoplasms / Q000503:physiopathology*; D002531:Cerebellum / Q000254:growth & development*; D004249:DNA Damage / Q000235:genetics; D017353:Gene Deletion; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins
keywords: CGNPs; Cerebellar neurogenesis; Division orientation; Medulloblastoma; Microcephaly; Mitosis