Nuclear respiratory factor-1 (NRF-1) is a major transcription factor in the human genome and functions in neurite outgrowth in neuroblastoma cells. Whether genes downstream from NRF-1 differentially regulate axonal and dendritic outgrowth in neurons remains largely unknown. Three hypothetical genes, C3orf10, FAM134C, and ENOX1, were investigated because their NRF-1 response elements are 100% conserved in humans and mice. We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. FAM134C but not C3orf10 mediates NRF-1-enhanced neurite outgrowth. In primary rat hippocampal neurons, Fam134c is predominantly expressed in the axon hillock and C3orf10 is ubiquitously expressed in all neurites and cell bodies at different developmental stages, suggesting their roles in axonal and dendritic outgrowth. Knockdown of Fam134c decreased both axonal length and the number of axonal collaterals and dendrites, however, knockdown of C3orf10 only increased the number of axonal collaterals and dendrites. Overall, we annotated FAM134C, C3orf10, and ENOX1 as NRF-1-regulated genes, which have differential effects on neurite outgrowth in neuroblastoma cells as well as neurons. This study provided an effective platform for annotating hypothetical genes in the human genome and increasing our knowledge in the molecular network underlying neuronal differentiation.
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