This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human SALL1 and SALL2P1 transription factors are abundantly expressed in human neural stem cells and in specific phenotypes within the mature human brain. However, these transcription factors are minimally expressed (SALL1) or not detectable (SALL2P1) in neuroblastoma cell lines. To determine the influence of these transcription factors on neural stem cell proliferation, and neural stem cell maturation into terminally differentiatted neurons, astrocytes and oligodendrocytes, experiments will be performed to establish in neural stem cells either continued SALL expression, or a state of SALL down-modulation. To permanently maintain SALL expression, normal human neural stem cells will be transfected with lentiviral-based expression vectors incorporating the gene for the SALL isoform (heterologous transgene expression). The reciprocal analysis, i.e., induction of 'loss-of-function' of a specific SALL isoform, will be mediated by RNA-mediated interference (RNAi). The knock-down of SALL isoform expression will be established either transiently, permanently, or via an inducible mechanism. The regulation of SALL isoform expression will allow us to examine whether these transcription factors influence: a) maintenance of a proliferative state in undifferentiated normal human neural stem cells; b) the profile of neural stem cells differentiating into neurons, astrocytes oroligodendrocytes; and c) maintenance of a differentiated phenotype in neurons, astrocytes and oligodendrocytes.
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