Posted August 19, 2013
Yuan Zhu, Ph.D., University of Michigan
Neurofibromatosis type 1 (NF1) is a complex genetic disorder characterized by the development of tumors in the nervous system. Often, affected children may also display a range of symptoms including bone abnormalities, larger-than-normal brain and head size, and accompanying learning disabilities. Clinical studies have shown that siblings with the same NF1 germline mutation may have dramatically different symptoms of the disease, indicating that the NF1 disease severity depends on other genetic and/or epigenetic factors. Dr. Yuan Zhu had previously used sophisticated genetic manipulations in mice to inactivate the Nf1 gene in neural stem cells during embryonic development and discovered that mice with inactivation of both copies of the Nf1 gene had enlarged brains soon after birth due to a dramatic increase in the number of glial cells in the corpus callosum, similar to the brain abnormalities observed in some human NF1 patients with severe learning deficits. With funding from an FY10 Investigator-Initiated Focused Research Award, Dr. Zhu used these mutant mice to perform preclinical studies using drugs currently in clinical trials for treating cancer.
To identify the molecular pathways that contribute to this brain abnormality defect in these mice, Dr. Zhu used immunohistochemical staining techniques to detect activation of intracellular signaling pathways associated with Nf1 in the mouse brain. He found that the ERK signaling pathway was activated in brain cells from neonatal and adult Nf1 mutant mice with enlarged brains, whereas other signaling pathways commonly activated in Nf1 tumors were not. These results suggest that drugs targeting the ERK signaling pathway might be useful as a treatment to prevent the brain abnormalities seen in these mice. Based on these findings, Dr. Zhu treated newborn Nf1 mutant mice with the MEK/ERK inhibitor PD0325901 for 18 to 21 days and found that it completely prevented the brain enlargement observed in these mutant mice. This study demonstrates that deregulated ERK signaling is critical for the development of some of the brain abnormalities associated with Nf1 gene inactivation, identifies a potential therapeutic agent (PD0325901), and highlights a window of opportunity for treating children with NF1-associated brain abnormalities.
Wang Y, Kim E, Wang X, et al. 2012. ERK inhibition rescues defects in fate-specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150(4):816-830.