A role for the ELAV RNA-binding proteins in neural stem cells: stabilization ofMsi1mRNA

Abstract

Post-transcriptional regulation exerted by neural-specific RNA-binding proteins plays a pivotal role in the development and maintenance of the nervous system. Neural ELAV proteins are key inducers of neuronal differentiation through the stabilization and/or translational enhancement of target transcripts bearing the AU-rich elements (AREs), whereas Musashi-1 maintains the stem cell proliferation state by acting as a translational repressor. Since the gene encoding Musashi-1 (Msi1) contains a conserved ARE in its 3′ untranslated region, we focused on the possibility of a mechanistic relationship between ELAV proteins and Musashi-1 in cell fate commitment. Colocalization of neural ELAV proteins with Musashi-1 clearly shows that ELAV proteins are expressed at early stages of neural commitment, whereas interaction studies demonstrate that neural ELAV proteins exert an ARE-dependent binding activity on the Msi1 mRNA. This binding activity has functional effects, since the ELAV protein family member HuD is able to stabilize the Msi1 ARE-containing mRNA in a sequence-dependent way in a deadenylation/degradation assay. Furthermore activation of the neural ELAV proteins by phorbol esters in human SH-SY5Y cells is associated with an increase of Musashi-1 protein content in the cytoskeleton. We propose that ELAV RNA-binding proteins exert an important post-transcriptional control on Musashi-1 expression in the transition from proliferation to neural differentiation of stem/progenitor cells.

Competing Interactions between Micro-RNAs Determine Neural Progenitor Survival and Proliferation after Ethanol Exposure: Evidence from anEx VivoModel of the Fetal Cerebral Cortical Neuroepithelium

“…Presenslin-1 deletion results in premature neuronal differentiation and suppression of miR-9 expression (Krichevsky et al, 2003), further supporting the involvement of the Notch pathway in ethanol's actions. In contrast to Jag-1, the brain-specific RNA binding protein ELAVL2, a presumptive target of miR-335, -153, and -9, promotes neuronal maturation by binding to the 3Ј untranslated regions of mRNAs to suppress non-neuronal fates and promote neuronal identity (Akamatsu et al, 1999(Akamatsu et al, , 2005Yano et al, 2005;Ratti et al, 2006). Previous evidence indicates that ELAVL2 also promotes neuron-specific alternate splicing and alternate polyadenylation (Zhu et al, 2007) to expand the transcriptome repertoire of neuron specific genes.…”

Downregulation of Msi1 suppresses the growth of human colon cancer by targeting p21cip1

“…It can be regulated by ELAV or HuR by maintaining the stabilization of its mRNA or accumulation of mRNA translation (7,8), as well as by tumor suppressor microRNAs (9). It was first found in Drosophila as a determinant of sensory organ development (10) and highly conserved across species (11) with essential roles in the stem cell maintenance, nervous system development and tumorigenesis (12,13).…”

Musashi Proteins in Neural Stem/Progenitor Cells

“…On the other hand, Ratti et al (2006) reported post-transcriptional regulation of Msi1 mRNA by embryonic lethal abnormal vision (ELAV), an RNA-binding protein of Drosophila (Ratti et al, 2006). This is an interesting result because it may imply that some kind of cascade of post-transcriptional regulation contributes to neurogenesis, in addition to other machinery, i.e., signal transduction, transcriptional regulation, and post-translational modification.…”