In the April 1st issue of Genes and Development, an international team of scientists lead by Dr. Luis Parada at the University of Texas Southwestern Medical School present an experimental mouse model of a prevalent human genetic disorder. Neuro-fibromatosis type 1 (NF1) is a neurologic disorder that affects 1 in 3,500 people world-wide. People with NF1 develop benign tumors along their peripheral and optic nerves, as well as caf-au-lait skin spots. NF1 is also associated with an increased risk of malignant neurological tumor development and childhood learning disabilities.
NF1 is one of the few diseases for which the underlying molecular mechanism is known. NF1 patients have defects in the NF1 gene, a tumor suppressor that negatively regulates the Ras protein. Ras acts as an intermediate between growth factor receptors on the outside of cells and the enzymatic cascade inside that activates genes required for cell proliferation and growth. NF1 is an essential checkpoint of Ras activity.
Previous attempts to create a mouse strain that lacks the NF1 gene have been unsuccessful because mutant mice die as embryos. However, using an advanced genetic engineering technique, Dr. Parada and his team were able to produce a strain of mice in which the NF1 ablation is restricted to mature neuronal cells only. This conditional NF1 knock-out thereby circumvents the embryonic lethality of a typical NF1 deficiency.
The NF1 deficient mice exhibited defective cerebral cortex development as well as an increased number of neural astrocyte cells. Although neurons of these mice exhibited increased Ras activity, the mice have not developed the tumors associated with NF1. However, NF1 deficient mice display severe learning disabilities and thus might present other clinical features of NF1. This conditional NF1 deficiency model will undoubtedly improve our understanding of the physiological role of NF1 and the progression of this common genetic disease.