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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.

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