Biology Reference
In-Depth Information
complexity that are essential for the dynamic nature of both the development
and activity of the nervous system.
1. Introduction
The large diversity of neuronal and nonneuronal cells that form a
nervous system arises from the combinatorial function of a large number of
gene regulatory factors. Nowadays, it is evident that these regulators include
not only transcription factors but also small regulatory RNAs, with micro-
RNAs (miRNAs) being the most intensely studied ones. While our under-
standing of transcription factor involvement in neural development far
exceeds that of miRNAs, here we review some of the more recent examples
of the roles of miRNAs in nervous system development.
miRNAs are an abundant class of short (21-23-nt long) regulatory
RNAs with versatile functions in biology (for review, see
Bartel, 2009
;
Chekulaeva and Filipowicz, 2009
). They are derived from longer primary
transcripts (pri-miRNA) that form stem-loop structures, through the
successive cleavages of two RNAse III-type enzymes. The first one,
Drosha, excises the hairpin structure (pre-miRNA) from the longer
pri-miRNA in the nucleus, while cleavage from the second one, Dicer,
in the cytoplasm results in the production of the mature 21-23-nt long
miRNA. Mature miRNAs associate with a protein complex with an
Argonaute family member at its core, and it is in the context of this
complex—also known as RNA-induced silencing complex (RISC)—that
miRNAs carry out their regulatory roles. miRNAs are, in the vast
majority of cases examined, negative regulators of their targets. In the
context of the RISC, miRNAs can guide binding to partially comple-
mentary sequences in their target mRNAs and cause posttranscriptional
repression of gene expression. The precise mechanism by which this
repression is exerted is still under debate. Both translational repression—
most likely at the level of translation initiation—and mRNA destabiliza-
tion—likely triggered by mRNA deadenylation—have been shown to
affect target protein levels. However, their relative contributions and
how they are mechanistically related to one another are still poorly
understood (for a recent review, see
Djuranovic
et al
., 2011
).
Regardless of our incomplete understanding of how miRNAs regulate
their targets, their cellular and physiological effects are evident. miRNAs
affect every step required for the proper development of a nervous system,
from patterning of the nervous system to neuronal differentiation and
plasticity. These functions have been described in nervous systems as simple
as that of
Caenorhabditis elegans
, where the first miRNA with a role in
neuronal differentiation was discovered (
Johnston and Hobert, 2003
), as
