Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene

Jeong Soo Lee, Arun Padmanabhan, Jimann Shin, Shizhen Zhu, Feng Guo, John P. Kanki, Jonathan A. Epstein, A. Thomas Look

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Neurofibromatosis type 1 is the most commonly inherited human cancer predisposition syndrome. Neurofibromin (NF1) gene mutations lead to increased risk of neurofibromas, schwannomas, low grade, pilocytic optic pathway gliomas, as well as malignant peripheral nerve sheath tumors and glioblastomas. Despite the evidence for NF1 tumor suppressor function in glial cell tumors, the mechanisms underlying transformation remain poorly understood. In this report, we used morpholinos to knockdown the two nf1 orthologs in zebrafish and show that oligodendrocyte progenitor cell (OPC) numbers are increased in the developing spinal cord, whereas neurons are unaffected. The increased OPC numbers in nf1 morphants resulted from increased proliferation, as detected by increased BrdU labeling, whereas TUNEL staining for apoptotic cells was unaffected. This phenotype could be rescued by the forced expression of the GTPase-activating protein (GAP)-related domain of human NF1. In addition, the in vivo analysis of OPC migration following nf1 loss using time-lapse microscopy demonstrated that olig2-EGFP+ OPCs exhibit enhanced cell migration within the developing spinal cord. OPCs pause intermittently as they migrate, and in nf1 knockdown animals, they covered greater distances due to a decrease in average pause duration, rather than an increase in velocity while in motion. Interestingly, nf1 knockdown also leads to an increase in ERK signaling, principally in the neurons of the spinal cord. Together, these results show that negative regulation of the Ras pathway through the GAP activity of NF1 limits OPC proliferation and motility during development, providing insight into the oncogenic mechanisms through which NF1 loss contributes to human glial tumors.

Original languageEnglish (US)
Pages (from-to)4643-4653
Number of pages11
JournalHuman Molecular Genetics
Volume19
Issue number23
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Fingerprint

Oligodendroglia
Zebrafish
Tumor Suppressor Genes
Cell Movement
Stem Cells
Cell Count
GTPase-Activating Proteins
Spinal Cord
Neurilemmoma
Neurofibromin 1
Optic Nerve Glioma
Neurons
Neurofibroma
Morpholinos
Neoplasms
Neurofibromatosis 1
In Situ Nick-End Labeling
Bromodeoxyuridine
Glioblastoma
Glioma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. / Lee, Jeong Soo; Padmanabhan, Arun; Shin, Jimann; Zhu, Shizhen; Guo, Feng; Kanki, John P.; Epstein, Jonathan A.; Thomas Look, A.

In: Human Molecular Genetics, Vol. 19, No. 23, 01.12.2010, p. 4643-4653.

Research output: Contribution to journalArticle

Lee, Jeong Soo ; Padmanabhan, Arun ; Shin, Jimann ; Zhu, Shizhen ; Guo, Feng ; Kanki, John P. ; Epstein, Jonathan A. ; Thomas Look, A. / Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 23. pp. 4643-4653.
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