Biology Reference
In-Depth Information
MHB along the antero-posterior axis. As mentioned, Fgf signaling from the
MHB to the surrounding area is critical for proper patterning around this
region, and it is in fact the target of mir-9 function. mir-9 seems to target
directly at least three components of the Fgf pathway,
fg fr-1, fg fr-8,
and
canopy
(
Leucht
et al
., 2008
). Interestingly, the patterning defect induced by
ectopic mir-9 can be fully rescued by protecting
fg fr-1
from mir-9 targeting,
arguing that most of the effect of mir-9 on the MHB is through this
pathway. Importantly, Fgf signaling is part of a feedback loop that ensures
MHB stability and mir-9 may be a part of such loop as well. Integration of
miRNAs into known gene regulatory networks is a key aspect of their
biological function and evolution and will be discussed in
Section 4
.In
addition to its effect on patterning, mir-9 also affects neurogenesis at the
boundary areas. This is a role for mir-9 that seems to be conserved in other
areas of the developing nervous system as well as across organisms and will
be discussed in
Section 2.1.2
.
Another well-characterized case of neural patterning during develop-
ment is the spatial organization of different neuronal and glial types in the
spinal cord. Two important mechanisms are used to define these diverse
progenitor domains. For dorso-ventral patterning, sonic hedgehog (SHH)
signaling from the ventral side of the neural tube and retinoic acid from the
mesoderm define five domains of ventral neural progenitors with charac-
teristic gene expression (for review, see
Jessell, 2000
). For antero-posterior
regionalization of the spinal cord, distinct domains of
Hox
gene expression
have been shown to be crucial (for review, see
Dasen and Jessell, 2009
).
Two cases have been described where miRNAs are proposed to ensure the
correct domains of expression in both mentioned aspects of spinal cord
patterning.
In the first case, mir-17-3p restricts the expression of transcription factor
OLIG2 to its known domain of expression (
Chen
et al
., 2011
). While
Olig2
is normally expressed in the ventral progenitor pool that gives rise to motor
neurons (pMN), it was also found to be transiently expressed in one of the
neighboring ventral pools that produce V2 interneurons (p2). However, for
p2 identity establishment,
Olig2
should be turned off and p2 cells should
express IRX3, another transcription factor that forms a cross-repressive loop
with OLIG2. mir-17-3p is expressed in the p2 domain (as well as in other
Irx3-positive pools) but not in the pMN domain. mir-17-3p can directly
repress
Olig2
, and thus, loss of this miRNA results in a significant loss of V2
interneurons due to ectopic expression of OLIG2 in the p2 pool.
In the second case, mir-196 has been implicated in the antero-posterior
patterning of the spinal cord. Although further evidence should be sought, it
seems likely that mir-196 delimits the domain of expression of
Hoxb8
in the
caudal neural tube to ensure
Hoxb8
is absent in the prospective hindlimb
field (
Asli and Kessel, 2010
). Ectopic HOXB8 expression in this lumbar area
causes a decrease in the number of motor neurons. However, the precise
