Biology Reference
In-Depth Information
contribution of mir-196 to this restriction is difficult to assess. A consistent
role for mir-196 in restricting
Hoxb8
expression had previously been
reported during limb formation, where
Hoxb8
is expressed in the forelimb
buds but not in the hindlimb buds (
Hornstein
et al
., 2005
). Loss-of-function
experiments knocking down mir-196 with an antagomir in developing
chick embryos showed derepression of
Hoxb8
at more anterior somites
consistent with a transformation of the last cervical vertebrae to a thoracic
identity (
McGlinn
et al
., 2009
). Interestingly, mir-196 has also been impli-
cated in proper tail and spinal cord regeneration following amputation in
axolotls (
Sehm
et al
., 2009
). However, in this case,
Hox
gene expression
does not seem to be the major target of mir-196.
Finally, the role of miRNAs in other patterning events, such as early
blastoderm organization in
Drosophila
(
Leaman
et al
., 2005
), neural tube
closure (
Maller Schulman
et al
., 2008
), and morphogenesis in the cortex and
hippocampus (
Davis
et al
., 2008
), have been proposed based on individual
miRNA knockdown, target-gene analysis, and conditional loss of Dicer,
respectively. These will not be discussed here, but further research in these
areas should prove interesting.
2.1.2. Neurogenesis
Neurogenesis is a tightly controlled process by which neuroepithelial pro-
genitors or other types of neural stem cells (NSCs), such as those involved in
adult neurogenesis, become progressively committed until becoming post-
mitotic neurons (for reviews, see
Conti and Cattaneo, 2010
;
Li and Jin,
2010
). Along their path to become neurons, NSCs have the choice of
proliferating to expand the progenitor pool or becoming more committed
neural precursor cells (NPCs). In addition, NPCs can give rise to either glial
cells (oligodendrocytes (OLs) and astrocytes) or neurons, and so during
neurogenesis, alternative fates must be repressed. Both intrinsic and extrinsic
factors are involved in these decisions. Among the intrinsic factors, the role
of miRNAs is becoming increasingly evident, with two miRNAs, mir-9
and mir-124, being extensively implicated in neurogenesis.
In NSCs from adult mouse forebrains, gain of function of mir-9 causes a
dose-dependent decrease in proliferation, and when these cells are induced to
differentiate, mir-9 can cause a marked increase in the percentage of differ-
entiated neurons and glia (
Zhao
et al
., 2009
). In addition, introduction of mir-9
in NSCs in developing mouse embryos (at E13.5) reduced their proliferation
and induced them to migrate to the cortical plate, as differentiated neurons do.
These cells also lost expression of a progenitor marker and instead expressed a
neuronal marker. A major target of mir-9 for these effects seems to be
the transcription factor TLX/Nr2e1, known to be required for stem-cell
renewal. Interestingly, TLX/Nr2e1 is a transcriptional repressor of mir-9-1
and mir-9-2 (there are three mir-9 encoding genes in the mouse genome),
thereby establishing a cross-repressive feedback loop.
