Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis

Abstract

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.HuD | neural stem cells | NeuroD1 | neurogenesis | SATB1

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy

“…Positive feedback loops are common in cellular signaling systems and can be established at the level of transcriptional regulation, post-transcriptional regulation, and posttranslational regulation [56][57][58][59]. Positive feedback loops are expected to lead to bistability and hysteresis [60][61][62].…”

Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision‐like Proteins?

“…Neuronal ELAV are key inducers of differentiation of neural progenitor cells . They have been identified as the first mammalian RBPs to be involved in memory, likely by affecting mRNA availability and/or protein synthesis in subcellular domains, thus contributing to the selective increase in synaptic strength .…”

“…These changes are the result of both transcriptional and post-transcriptional control of gene expression, although only post-transcriptional mechanisms allow a precise and localized modulation of those biochemical events, which occur during learning at synaptic level. Neuronal ELAV are key inducers of differentiation of neural progenitor cells [80]. They have been identified as the first mammalian RBPs to be involved in memory, likely by affecting mRNA availability and/or protein synthesis in subcellular domains, thus contributing to the selective increase in synaptic strength [81,82].…”

RNA regulation went wrong in neurodevelopmental disorders: The example of Msi/Elavl RNA binding proteins

“…Their dendrite arborization is reduced to a lesser extent, suggesting that Elavl4 functions in the dendritogenesis of specific neuronal subtypes (Deboer et al, 2014). More recent publication provides a novel model of Elavl4 dependent adult neurogenesis, such that transcriptional factor SATB1 promotes the Elavl4 expression, while Elalv4 stabilize SATB1 mRNA during neurogenesis of adult neural stem cells through SATB1‐NeuroD axis, thereby forming the positive feedback‐loop between Elavl4 and the transcriptional factors (Wang et al, 2015). On the other hands, the Elavl3 single mutant and haplo‐insufficient heterozygous mutant show spontaneous epilepsy.…”