Zebrafish Neurofibromatosis Type 1 Models

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. The disease is caused by mutations in the NF1 gene, which encodes the large protein neurofibrin, which contains a GTPase-activating protein-associated domain that inactivates the RAS proto-oncogene. Loss of NF1 results in aberrant activation of Ras signaling, which may predispose NF1 patients to a variety of cancers. Affected individuals exhibit abnormalities in neural crest-derived tissue, including pigmented skin lesions and benign peripheral nerve sheath tumors. Patients with NF1 are also prone to malignancies, including juvenile myelomonocytic leukemia, optic glioma, glioblastoma, schwannoma, and malignant peripheral nerve sheath tumor.

Considerable efforts have been made to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, but the key signaling pathways that control tumorigenesis and progression remain to be elucidated. An animal model that facilitates rapid interrogation of epistasis and functional relationships within signaling pathways will be a valuable tool for exploring the pathological basis of NF1-induced cellular transformation. While mouse and Drosophila models of NF1 have proven informative, one would like to gain more information from alternative model systems. In particular, vertebrate models that allow high-throughput in vivo screening and rapid, cost-effective phenotyping may aid in the discovery of new functional and therapeutic approaches.

Fig.1 Zebrafish have two orthologues of human NF1.

Our Zebrafish Neurofibromatosis Type 1 Models

Creative Biogene employed a targeted mutagenesis strategy to generate zebrafish with stable germline mutations in the NF1 orthologs nf1a and nf1b. The phenotype of the mutant larvae resembled aspects of human disease and resulted in larval lethality within 7 to 10 days of fertilization. NF1-null larvae display marked central and peripheral nervous system defects, abnormal proliferation and differentiation of oligodendrocyte progenitors, malformed myelin sheaths, and hyperplasia of Schwann cells.

We are committed to elucidating novel developmental functions of neurofibromin through the zebrafish NF1 model system, facilitating the identification of modifier genes affecting NF1 pathogenesis, helping you better understand the molecular and cellular determinants of NF1 disease pathogenesis in vivo, and, in addition, The feasibility of high-throughput chemical screening using our model should provide additional valuable mechanistic insights and identify lead compounds for future treatments. We aim to provide a platform for further study of one of the most common clinicopathologies associated with NF1.

Advantages

• Easy observation of tumorigenesis and tumor-induced phenotypes in live animals
• Multiple induction models
• Mass mutagenesis
• High-throughput gene/drug screening

References

1. Shin J, et al. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Dis Model Mech. 2012, 5(6):881-894.
2. Padmanabhan A, et al. Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci U S A. 2009, 106(52):22305-22310.

For research use only. Not intended for any clinical use.