Zebrafish model of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1), a common inherited disorder, causes skin-pigmentation and CNS abnormalities, and increases the risk of developing several types of cancer. It varies widely in clinical presentation, even in family members carrying an identical mutation at the NF1 locus, suggesting genetic or environmental modifiers. To probe underlying mechanisms, Shin, Padmanabhan et al. studied the zebrafish homologues of human NF1 – nf1a and nf1b – and used targeted approaches to create nf1-null zebrafish, which showed melanophore defects and a range of CNS abnormalities at the larval stage. As hypothesised for human NF1, zebrafish nf1 genes also act as tumour suppressors: nf1-null larvae showed hyperactivation of Ras in the spinal cord, and combined loss of nf1 and p53 accelerated tumorigenesis. These data indicate that zebrafish nf1a and nf1b are tumour suppressors with crucial roles in CNS development. This is also the first animal model of NF1 in which pigmentation defects – an important feature of the human disease – have been documented. Page 881