期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：E4995-E5004
DOI：10.1073/pnas.1513780112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceRNA-binding proteins play central roles in posttranscriptional gene regulation. HuD is one of the first markers used for neuronal lineage; however, the function of HuD in neural stem cell differentiation is largely unexplored. In addition, although it has been shown that HuD mRNA levels increase during neuronal differentiation, to date few studies have examined the mechanism controlling the expression of HuD during neural differentiation. In this study, we investigated the role of HuD in neural stem cell differentiation and uncovered an underlying molecular mechanism. Our results unveil a novel positive feedback network between an RNA-binding protein and a transcription factor that plays critical regulatory roles during neuronal differentiation. The mammalian embryonic lethal abnormal vision (ELAV)-like protein HuD is a neuronal RNA-binding protein implicated in neuronal development, plasticity, and diseases. Although HuD has long been associated with neuronal development, the functions of HuD in neural stem cell differentiation and the underlying mechanisms have gone largely unexplored. Here we show that HuD promotes neuronal differentiation of neural stem/progenitor cells (NSCs) in the adult subventricular zone by stabilizing the mRNA of special adenine-thymine (AT)-rich DNA-binding protein 1 (SATB1), a critical transcriptional regulator in neurodevelopment. We find that SATB1 deficiency impairs the neuronal differentiation of NSCs, whereas SATB1 overexpression rescues the neuronal differentiation phenotypes resulting from HuD deficiency. Interestingly, we also discover that SATB1 is a transcriptional activator of HuD during NSC neuronal differentiation. In addition, we demonstrate that NeuroD1, a neuronal master regulator, is a direct downstream target of SATB1. Therefore, HuD and SATB1 form a positive regulatory loop that enhances NeuroD1 transcription and subsequent neuronal differentiation. Our results here reveal a novel positive feedback network between an RNA-binding protein and a transcription factor that plays critical regulatory roles in neurogenesis.
