Reciprocal actions of REST and a microRNA promote neuronal identity

Abstract

MicroRNAs (miRNAs) are implicated in both tissue differentiation and maintenance of tissue identity. In most cases, however, the mechanisms underlying their regulation are not known. One brainspecific miRNA, miR-124a, decreases the levels of hundreds of nonneuronal transcripts, such that its introduction into HeLa cells promotes a neuronal-like mRNA profile. The transcriptional repressor, RE1 silencing transcription factor (REST), has a reciprocal activity, inhibiting the expression of neuronal genes in nonneuronal cells. Here, we show that REST regulates the expression of a family of miRNAs, including brain-specific miR-124a. In nonneuronal cells and neural progenitors, REST inhibits miR-124a expression, allowing the persistence of nonneuronal transcripts. As progenitors differentiate into mature neurons, REST leaves miR-124a gene loci, and nonneuronal transcripts are degraded selectively. Thus, the combined transcriptional and posttranscriptional consequences of REST action maximize the contrast between neuronal and nonneuronal cell phenotypes.noncoding RNA ͉ repression ͉ neuronal phenotype

New meaning in the message: Noncoding RNAs and their role in retinal development

“…Translation of Rdh10, a retinol dehydrogenase that is selectively expressed in Muller glia and RPE, was found to be directly repressed by miR-124a in rats (Arora et al, 2007). This finding fits well with the previously demonstrated role of this miRNA in repressing non-neuronal transcripts (Conaco et al, 2006).…”

MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

“…In contrast, the same target sequences would be expected to have nucleotides at positions one and two unpaired in a duplex with miR-124-UU21, likely reducing or preventing inhibition by miR-124-UU21. The Itgb1 mRNA is downregulated by miR-124 [41,43,44]. The 3'UTR of mouse Itgb1 contains two putative miR-124 binding sites in which the 3' nt of each putative target site is mismatched with the terminal 5' nt of miR-124, while miR-124-UU21 is mismatched with the two terminal 5' nt (Fig.…”

“…The expression of mammalian miR-124 can be first detected in differentiating neurons and persists in mature neurons, suggesting that miR-124 plays important roles during neural development [25,28,37,39,40]. The expression of miR-124 appears in part to mediate the repression of non-neuronal genes in neurons [41][42][43], as well as the downregulation of genes expressed in neural progenitors [44]. Overexpression of miR-124 (and other brain-enriched miRNAs) in mouse embryonic stem cells promotes neuronal fates [45], and a recent study indicates that miR-124 can promote neuronal differentiation via inhibition of the Ctdsp1/SCP1 phosphatase, a component of the REST/NRSF transcriptional repression complex [46].…”

Principles of micro-RNA production and maturation

“…These are the characteristics of RNA polymerase II (Pol II) transcripts such as pre-mRNAs. In addition, multiple studies have characterized, at least partially, the promoters that direct miRNA transcription (Johnson et al, 2003;Johnston and Hobert, 2003;Cai et al, 2004;Lee et al, 2004;Fazi et al, 2005;Houbaviy et al, 2005;O'Donnell et al, 2005;Sokol and Ambros, 2005;Zhao et al, 2005;Conaco et al, 2006). These promoters also bear the hallmark of Pol II promoters.…”