Identification of miRNAs with critical function in neurogenesis and oncogenesis

Abstract

MicroRNAs (miRNAs) have been reported to play critical roles in regulating brain development and synaptic plasticity. Previous findings demonstrating the involvement of specific miRNAs in several neurological disorders encouraged us to pursue the etiological connections between altered expression/ functioning of certain miRNAs, neurogenesis and brain tumor formation. We propose to identify specific miRNAs playing critical role in the process of neurogenesis and their possible linkage with abnormal neoplastic transformation in human embryonic stem cell (hESC)-model. Furthermore, attempts will be made to identify miRNA specific targets of up/ down stream signaling pathway(s) using knock-in/ knock-out approaches. Once the role of specific miRNA is identified under in vitro conditions, the involvement of these miRNA will be confirmed using in vivo models by two approaches i.e., studying miRNA induced neural differentiation of hESCs and identification of their target genes and gene products; and studying the association of identified miRNAs in neoplastic transformation with special reference to events involved in self-renewal and differentiation capacities. Perhaps, the study will be the first of its own kind to establish the links between human brain specific miRNAs and regulation of specific events and pathways associated with neuronal lineage specific development as well as brain tumor formation and extrapolation of in vitro findings to the in-life situations in rodent model. The outcome of the study will also provide a novel avenue and baseline data to extend the approaches towards the identification and development of miRNAs as ''molecular tools'', with the potential to address novel molecular pathways involved in neurogenesis and to generate new molecular-bases to understand early steps during neurogenesis as well as brain cancer initiation.