c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain.
myc genes are associated with a wide variety of human cancers including most types of nervous system tumors. While the mechanisms by which myc overexpression causes tumorigenesis are multifaceted and have yet to be clearly elucidated, they are at least in part related to endogenous myc function in normal cells. Knockout (KO) of either c-myc or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre impairs mouse brain growth and mutation of N-myc also causes microcephaly in humans in Feingold Syndrome. To further define myc function in NSC and nervous system development, we created a double KO (DKO) for c- and N-myc using nestin-cre. The DKO mice display profoundly impaired overall brain growth associated with decreased cell cycling and migration of NSC, which are strikingly decreased in number. The DKO brain also exhibits specific changes in gene expression including downregulation of genes involved in protein and nucleotide metabolism, mitosis, and chromatin structure as well as upregulation of genes associated with differentiation. Together these data support a model of nervous system tumorigenesis in which excess myc aberrantly locks in a developmentally active chromatin state characterized by overactive cell cycling, and metabolism as well as blocked differentiation.
Wey
Alice
A
Institute of Pediatric Regenerative Medicine, Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Shriners Hospital For Children Northern California, Sacramento, CA 95817, USA.
Knoepfler
Paul S
PS
D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002453:Cell Cycle; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D004380:Duodenal Obstruction / Q000235:genetics; D004933:Esophageal Atresia / Q000235:genetics; D005143:Eyelids / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008607:Intellectual Disability; D007381:Intermediate Filament Proteins / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064231:Nestin; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014138:Tracheoesophageal Fistula
D002843:Chromatin; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016271:Proto-Oncogene Proteins c-myc