A Small Modulatory dsRNA Specifies the Fate of Adult Neural Stem Cells

Abstract

Discovering the molecular mechanisms that regulate neuron-specific gene expression remains a central challenge for CNS research. Here, we report that small, noncoding double-stranded (ds) RNAs play a critical role in mediating neuronal differentiation. The sequence defined by this dsRNA is NRSE/RE1, which is recognized by NRSF/REST, known primarily as a negative transcriptional regulator that restricts neuronal gene expression to neurons. The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the transition from neural stem cells with neuron-specific genes silenced by NRSF/REST into cells with neuronal identity that can express neuronal genes. The mechanism of action appears to be mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA. The discovery of small modulatory dsRNAs (smRNAs) extends the important contribution of noncoding RNAs as key regulators of cell behavior at both transcriptional and posttranscriptional levels.

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

“…Evf-2 thus appears to be acting at least partially as a RNA-based transcriptional coactivator. This potential function is not unprecedented, as the ncRNA SRA has been known for some time to act as a transcriptional coactivator by directly interacting with steroid receptors (Lanz et al, 1999), while the ncRNAs NRSE and HSR have been shown to regulate the activity of REST and HSF-1, respectively (Kuwabara et al, 2004;Shamovsky et al, 2006). However, the story is likely more complex for Evf-2.…”

Expanding the ‘central dogma’: the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia

“…Pertinent examples are discussed above, although numerous other ncRNA regulatory mechanisms exist. 31,46,5,8 The following examples, while speculative in nature, are meant to illustrate how altered regulation of mRNA expression could potentially play a role in schizophrenia risk. Similar mechanisms could also contribute to the risk of other complex brain disorders, especially those with a neurodevelopmental etiology.…”

“…4 For example, ncRNA may regulate protein synthesis by decelerating or accelerating mRNA degradation. [5][6][7][8] Control mechanisms may target the mRNA degradation enzymes or some other aspect of the propensity of the mRNA to be degraded, thus impacting the steady concentration (ie 'half-life') of the mRNA. 9 These newly discovered control mechan-isms for protein expression are often referred to as the 'tip of the iceberg', anticipating that yet undiscovered regulatory functions of ncRNAs are likely to be critical to the development and function of complex organisms.…”

Epigenetics and neural stem cell commitment

“…It is suggested that most of the currently characterized small, non-coding RNAs play roles in transcriptional gene silencing. Kuwabara et al reported that non-coding RNAs could also function in activating neuron-specific gene expression [54] . 5.2 NRSE/NRSF interaction Many neuronal genes are repressed in the non-neuronal cells by a conserved neuron restrictive silencer element or repressor element-1 (NRSE/ RE1), which interacts with a zinc-finger protein known as neuronal restricted silencing factor or RE-1 silencing transcription factor (NRSF/REST).…”

“…Cecilia and colleagues demonstrated the reciprocal actions of NRSF, and proved that miRNAs could promote neuronal identity [67] . All of these data suggest that small, non-coding RNAs have diverse modulation functions in development and stem cell biology, and they regulate cell behavior at both transcriptional and posttranscriptional levels [54] . …”