Direct conversion techniques, which generate induced-neuronal (iN) cells from human fibroblasts in less than two weeks, are expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression and cell morphology profiles in iN cells derived from neurofibromatosis type 1 (NF1) patients. NF1 is a single-gene multifaceted disorder with relatively high co-occurrence of autism spectrum disorder (ASD). Adenylyl cyclase (AC) dysfunction is one of the candidate pathways in abnormal neuronal development in the brains of NF1 patients. In our study, microarray-based transcriptomic analysis of iN cells from healthy controls (males) and NF1 patients (males) revealed significantly different gene expression of 149 (110 were upregulated and 39 were downregulated). In iN cells derived from NF1 patients (NF1-iN cells), there was a change in the expression level of 90 genes with the addition of forskolin, an AC activator. Furthermore, treatment with forskolin dramatically changed the cell morphology, especially that of NF1-iN cells, from flat-form to spherical-form. Current pilot data indicate the potential therapeutic effect of forskolin or AC activators on neuronal growth in NF1 patients. Further translational research is needed to validate the pilot findings for future drug development of ASD.
Part of the book: Clinical and Basic Aspects of Neurofibromatosis Type 1