Biomedical Engineering Reference
In-Depth Information
4. CELSR1
-
3 IN NEURONAL MIGRATION
The migration of facial branchiomotor (FBM) neurons in the devel-
oping rhombencephalon is an intriguing case that combines tangential and
radial migration modes. FBM neurons, which innervate muscles responsible
for facial expression (
Chandrasekhar, 2004; Garel, Garcia-Dominguez, &
Charnay, 2000; Guthrie, 2007
), are generated in medial rhombomere4
(r4) at E10.5 and immediately extend their axons laterally toward muscle
targets. At E11.5, their cell bodies initiate a tangential caudal migration
from r4 to r6. They migrate in the subventricular region, pass medial to
the nucleus abducens (nVI) in r5 (
Song et al., 2006
), and then move
laterally and dorsally in r6. Finally, they undergo a radial migration in r6
to reach their subpial location where they form the motor nucleus of the
facial (nVII) nerve (
Fig. 7.4A
)(
Chandrasekhar, 2004
). The caudal soma
translocation of FBM neurons, with looping of their axons (so-called
genu
of facial nerve) is conserved from fish to mammals, with important
species differences. For example, it is blunted in chick (
Gilland & Baker,
2005
). The first indication that
Celsr
genes are involved in FBM neurons
migration came from an ENU mutagenesis screen in zebrafish that
identified four point mutations in the
Celsr2
/
off road
locus (
Wada et al.,
2006
). In these mutants, FBM neurons fail to migrate caudally to r6,
moving instead prematurely into lateral r4-r5. Morpholino knockdown
experiments showed that
Celsr1a
and
1b
have adjunct functions in FBM
neuron migration. Whereas combined downregulation of
Celsr1a
and
Celsr1b
has little effect on its own, it worsens the
off road
mutant
phenotype, with more cells stacked in r4 in
Celsr1a
;
Celsr1b
;
Celsr2
triple
mutants than in
Celsr2
mutants. In mice, FBM neuron migration was
studied using
in situ
hybridization for
Islet1
or
Tbx20
, two established
markers. In wild-type embryos, FBM neurons form streams from medial
r4 to lateral r6, with a sharp rostral edge. In
Celsr1
ko/ko
mice, FBM
neurons are still able to move out of r4, but a subset migrate rostrally into
r3 and r2 rather than caudally, a phenotype never seen in any other
vertebrate. This rostral migration phenotype is fully penetrant, although
with variable expressivity. Caudally directed
Celsr1
ko/ko
neurons move
through r5, medially to the abducens nucleus (nVI), before moving
laterally in r6 like their wild-type counterparts. Hence, a facial (nVII)
nucleus forms in its normal location in lateral r6 by E13.5. In addition,
rostrally migrating FBM neurons form an ectopic nucleus adjacent or
