N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation

Paul S Knoepfler, Pei Feng Cheng, Robert N. Eisenman

Research output: Contribution to journalArticle

361 Scopus citations

Abstract

To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene. Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization. In control mice at E12.5, we observe a domain of high N-Myc protein expression in the rapidly proliferating cerebellar primordium. Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected. Null progenitor cells also have comparatively high levels of the cdk inhibitors p27Kip1 and p18Ink4c, whereas p15Ink4b, p21Cip1, and 19Ink4d levels are unaffected. Many null progenitors also exhibit altered nuclear morphology and size. In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker βTUBIII in the cerebrum. Furthermore, in progenitor cell cultures derived from null embryonic brain, we observe a dramatic increase in neuronal differentiation compared with controls. Thus, N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size. Its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)2699-2712
Number of pages14
JournalGenes and Development
Volume16
Issue number20
DOIs
StatePublished - Oct 15 2002
Externally publishedYes

Keywords

  • cdk inhibitors
  • Cerebellum
  • Conditional knockout
  • Cyclin D2
  • N-myc
  • Nervous system

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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