Generation of a zebrafish neurofibromatosis model via inducible knockout ofnf2

Abstract

SummaryNeurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout ofnf2a/b, the zebrafish homolog of human NF2. Analysis ofnf2aandnf2bexpression reveals ubiquitous expression ofnf2bin the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast,nf2adisplays lower expression levels. Induction ofnf2a/bknockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish,nf2a/bknockout triggers the development of a spectrum of tumors, including vestibular schwannomas, spinal schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.