Examining the role of SoxC transcription factors in adult hippocampal neuronal differentiation.

Adult neurogenesis has been suggested to play a role in learning, memory, and depression. While the observation and characterization of adding new neurons to adult hippocampus has been robust, the underlying regulatory mechanisms remain poorly understood. There are two fundamental questions for understanding the molecular code of adult neurogenesis: 1) Which transcription factors regulate it?; 2) What is their mode of action? I attempted to work out these two questions by focusing on SoxC group of transcription factors, Sox4 and Sox11. Their role in embryonic neurogenesis has been evidenced by findings that SoxC members are specifically expressed in the developing mouse central nervous system and chicken spinal cord and are functionally redundant. Meanwhile, our laboratory suggested that SoxC proteins could also regulate adult neurogenesis. In this study I give evidence that Sox4 and Sox11 are essential regulators of adult hippocampal neurogenesis. This conclusion is supported by the following observations. First, I found that Sox4 and Sox11 protein expression in adult hippocampus was initiated upon neuronal fate commitment. Second, my in vitro experiments showed that Sox4 and Sox11 potently induced neuronal differentiation of adult neural stem cells. In addition, Sox4 and Sox11 directly activated the promoter of the neuronal lineage-specific gene DCX. Third, my in vivo experiments showed that the loss of Sox4 and Sox11 abolished the expression of neuron-specific structural protein DCX in adult mouse hippocampus . Moreover, overexpressing Sox11 in adult neurogenic niche prolonged the DCX expression, shifted the cell position towards the outmost region of granule cell layer, but did not affect dendritic length and branching. Finally, I found that Sox2 might be one of the activators of Sox11 transcription in adult hippocampal neurogenic lineage. Based on these findings, I demonstrated a crucial role of SoxC factors in adult hippocampal neurogenesis. Given the emerging role of dysfunctional hippocampal neurogenesis in Alzheimer’s disease, epilepsy and depression, the data raises the possibility that dysregulation of SoxC activity could be involved in hippocampus-associated pathological processes.&nbsp