Biology Reference
In-Depth Information
(
Siegel
et al
., 2009
) and cardiac patterning (
Morton
et al
., 2008
). As men-
tioned, mir-338 is involved in OL differentiation but plays a role in axonal
function as well (
Aschrafi
et al
., 2008
), while mir-132 in addition to its role
in dendritic outgrowth also modulates circadian rhythms and has a function
in innate immunity (
Cheng
et al
., 2007
;
Lagos
et al
., 2010
).
A few studies have uncovered that the same miRNA can have different
effects in different time points along the development of the same tissue.
mir-124 seems to have two different effects during eye development in
Xenopus.
During the optic vesicle stage, mir-124 is necessary and sufficient
to repress neurogenesis and promote proliferation of retinal progenitors (
Liu
et al
., 2010
). This effect is at least in part through the repression if
NeuroD1
,a
known inducer of neuronal differentiation. Interestingly, if after injection
with mir-124 for overexpression animals are examined later, at the optic
cup stage, a reduction in cell proliferation is observed, more consistent with
the role of mir-124 in promoting neurogenesis presented above (
Qiu
et al
.,
2009
). While further work is necessary to explore whether this later effect of
mir-124 is due to a direct effect on proliferation or a consequence of its
earlier effect on the progenitor pool, it is interesting to note that careful
temporal analysis of miRNA function could address some of the discrepan-
cies mentioned above (e.g.,
Section 2.1.2
).
Another interesting case came from a study in
Xenopus,
where loss of mir-9
caused different effects on neurogenesis in neural progenitors from the fore-
brain as compared to those in the hindbrain (
Bonev
et al
., 2011
). In the
hindbrain, knockdown of mir-9 caused an increase in proliferation of neural
progenitors, consistent with its role in limiting proliferation and promoting
differentiation in other organisms. In contrast, in the forebrain, knockdown of
mir-9 reduced the number of progenitors due to increased apoptosis, but
when apoptosis was blocked, a similar increase in progenitor proliferation was
observed. Interestingly, in both cases, mir-9 seems to exert its function
through the repression of
hairy1,
and protection of
hairy1
from mir-9 repres-
sion phenocopies both the increased proliferation in the posterior progenitors
and the increased apoptosis in the anterior progenitors. This suggests that the
specificity of function is downstream of the miRNA target and that context-
dependent functions can arise through a variety of mechanisms.
Finally, a given miRNA can cause different effects even within the same
cell. This is of particular relevance to neurons, where localization in differ-
ent cellular compartments can lead to distinct functions. One example
presented above is that of mir-134 which localizes to puncta in the dendritic
terminals of neurons where it can have a local effect on the strength of
individual spines by targeting Limk1 but also seems to be able to cause more
global effects on dendritic outgrowth by targeting a more general regulator,
Pumilio2 (
Khudayberdiev
et al
., 2009
).
The fact that miRNAs have functions that can be so dependent on the
cellular context is consistent with a number of observations that suggest that
