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In-Depth Information
In another report using hESC-derived hNPCs, loss-of-function analysis
of mir-9 revealed a somewhat different role. First, mir-9 was necessary for
the proliferation of the hNPCs (
Delaloy
et al
., 2010
). In addition, in the
hESC-derived hNPCs, mir-9 inhibits neuronal migration by repressing
Stathmin, a protein that increases microtubule instability. While the oppos-
ing effect of mir-9 in these two experimental setups could well be due to
their inherent differences (perhaps the main difference is the origin of the
studied progenitors), it is also possible that mir-9 gain- (in
Zhao
et al
., 2009
)
and loss-of-function (in
Delaloy
et al
., 2010
) studies have uncovered differ-
ent functions for this versatile miRNA, and that its effect on proliferation
and differentiation results from the balance of its different targets at different
developmental stages or in different neuronal or neuronal progenitor types.
Further experiments with emphasis on comparing the function of miRNAs
along different precursor or mature states of different types of neurons
should clarify these discrepancies.
In vivo
studies in vertebrate systems have been more consistent with a
role for mir-9 as a promoter of neurogenesis, mostly by repressing inhibitors
of neuronal differentiation. In mouse and zebrafish, mir-9 is found in
proliferating progenitor cells as well as in mature neurons (
Lagos-
Quintana
et al
., 2002
;
Leucht
et al
., 2008
;
Wienholds
et al
., 2005
). As
mentioned above, mir-9 is expressed in the NPCs just outside the zebrafish
MHB where it represses the antineurogenic Hes bHLH transcription factors
her5
and
her9
, thereby promoting differentiation. This effect of mir-9 also
explains why its ectopic expression causes loss of the MHB: not only does it
repress MHB required genes, but it also causes premature differentiation and
thus depletion of the progenitor pool in the MHB. In
Xenopus
, mir-9 has
also been implicated in promoting neurogenesis through the inhibition of
hairy1
, another member of the Hes bHLH transcriptional repressors (
Bonev
et al
., 2011
).
In the developing mouse brain, mir-9 function has been most extensively
studied in the telencephalon. Using gain- and loss-of-function experiments
by injection of mir-9 or a mir-9 antisense oligonucleotide, respectively,
and more recently analysis of a mir-9-2/mir-9-3 double mutant mouse,
Aizawa and colleagues have shown that mir-9 promotes differentiation of
Cajal-Retzius cells in the medial pallium as well as other early-born neurons
(E12.5-E13.5) (
Shibata
et al
., 2008, 2011
). This early effect seems to be
mediated by repression of
Foxg1
by mir-9. FOXG1 is a forkhead transcrip-
tion factor with a known role in promoting proliferation of progenitor cells,
and in the medial pallium, the expression patterns of mir-9 and
Foxg1
form reciprocal gradients. Interestingly, no effect on TLX/Nr2e1 was
observed in these studies. In the absence of mir-9, increased proliferation
of early-differentiating neural progenitors is observed in the medial pallium
and also in the subpallium (in this case, mir-9 seems to target both
Foxg1
and
Gsh2
). Interestingly, in the mir-9-2/3 mutant at later stages (E16.5-E18.5),
