Microarray Analysis of VHL-gene-transferred Neural Stem Cells Around Transcriptional Signaling Pathways of Neuronal Differentiation

Abstract Previously, we reported that the von Hippel-Lindau (VHL) tumor suppressor gene induces neural stem cell (NSC) differentiation to neurons, and that VHL's involvement in differentiating NSCs or mesenchymal stem cells (MSCs) into neurons is related to the inhibition of the JAK/STAT pathway through the proteasomal degradation of proteins following their ubiquitination by the VHL/ elonginBC/Cul2 complex. However, the relationship between VHL and other pathways and factors around VHL-mediated neuronal differentiation is still unclear. In this study, the VHL gene was transferred to adult rat NSCs, and the gene expression profiles of the VHL-gene-transferred and control NSCs were analyzed using cDNA arrays. Then, the genes of the transcriptional signaling pathways around the VHL gene were examined. In particular, we examined the expression profiles of VHL-downstream genes, neurogenesis genes, hormonal genes, cytokine genes, and ubiquitin/ proteasome genes. VHL-transfected NSCs showed increased expression of most neurochemical and neurogenesis genes, hormonal genes, homeobox genes, and cytokine genes. However, they showed decreased expression of VHL-downstream genes (HIF/VEGF/EPO, JAK/STAT/Smad), neurogenesis-associated genes (Wnt, Notch, and GFAP), and ubiquitin/proteasome genes. Meanwhile, the expression of neurotrophic factors was either increased or decreased. cDNA microarray analysis revealed that VHL not only regulates neuronal differentiation and the HIF/ VEGF/EPO and JAK/STAT/Smad pathways but also development, hormones, and cytokines. Understanding the transcriptional signaling pathways around VHL that induce neuronal differentiation is very important in neuronal regenerative medicine.