Children with Neurofibromatosis type 1 (NF1) are prone to the development of clinical problems that reflect abnormalities in both nerve cell (learning and behavior) and glial cell (brain tumors) function. In this regard, nerve cells and glial cells originate from stem cells in the brain (called neural stem cells); however, it was not known how the NF1 gene precisely controlled neural stem cell (NSC) growth and differentiation (the formation of nerve and glial cells).
Yi-Hsien Chen, a post-doctoral fellow in the laboratory of Dr. David Gutmann, used a combination of experimental strategies to demonstrate that the NF1 gene regulates NSC growth and differentiation by shutting off the activity of the RAS protein. Importantly, Dr. Chen found that the decision to form more NSCs versus differentiate into nerve and glial cells are controlled by two different RAS signaling pathways. In this study, he showed that RAS control of NSC growth is mediated by the AKT molecule, whereas NSC differentiation is regulated by the MEK signaling pathway. In addition, Dr. Chen discovered that MEK controls NSC formation of new nerve and glial cells through a mechanism not previously ascribed to NF1.
Together, these novel findings clearly establish that NF1 gene control of brain stem cell function operates through distinct RAS signaling pathways, which can be individually targeted to block abnormal cell growth or differentiation.
Dr. Chen’s paper was published in the journal, Genes and Development.
Chen YH, Gianino SM, Gutmann DH. Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways. Genes Dev. 2015; doi:10.1101/gad.261677.115.