Biomedical Engineering Reference
In-Depth Information
Early observations showed that
fmi/stan
is essential for the development
of axonal tracts. Null mutations
fmi
E45
and
fmi
E59
are embryonic lethal, and
in addition to PCP defects, mutant embryos display abnormalities in longi-
tudinal axonal tracts. Rescue of axonal, but not PCP defects, by brain spe-
cific expression of the
fmi
cDNA restores viability (
Usui et al., 1999
).
Subsequent elegant studies in the visual system showed that fmi/stan medi-
ates axon-axon and axon-target interactions required for guidance of pho-
toreceptor axons (
Lee et al., 2003; Senti et al., 2003
). The fmi-mediated
choice of postsynaptic target is dose dependent and non-cell autonomous.
It looks as if growth cones “compare” their fmi/stan levels with that of
their neighbors to “decide” whether to establish contact or not (
Chen &
Clandinin, 2008
). In mice,
Celsr3
is crucial for axon guidance.
Celsr3
mutant mice display marked defects in major tracts such as the anterior
commissure, internal capsule, medial lemniscus, and corticospinal tract
(
Table 7.1
).
Celsr3
is also essential for the anterior-posterior organization
of monoaminergic axon in the brainstem (
Fenstermaker et al., 2010
) and
for the rostral turning of commissural axons after midline crossing in the
spinal cord (
Price et al., 2006; Wang & Nathans, 2007
). Celsr3 deficiency
does not affect axonal growth
per se
, but rather guidance, resulting in
stalling at intermediate targets or misrouting of axons (
Tissir, Bar, Jossin,
De Backer, & Goffinet, 2005
). For instance, during development of
corticothalamic reciprocal projections, mutant corticofugal axons travel
normally in the subcortical layer but stall underneath the pallial-subpallial
boundary. Reciprocally, thalamic axons never reach their cortical targets
in layer 4; instead, they course ventrally along the hypothalamus and then
turn externally toward the cortical marginal zone. Conditional removal of
Celsr3
in a stream that extends in the basal forebrain and ventral
diencephalon precludes the entry of corticosubcortical and
thalamocortical fibers in the “corridor” and results in defective internal
capsule. This result demonstrates that
Celsr3
is required in intermediate
targets to connect the cortex with subcortical structures. Target cells are
molecularly defined by expression of Dlx5/6 and qualify as “guidepost
cells” (
Zhou et al., 2008
). To test whether guidance of cortifugal axon is
mediated by homophilic interactions of
Celsr3
in navigating growth
cones and guidepost cells,
Celsr3
was specifically deleted in corticofugal
axons by crossing the
Celsr3
f
allele with
Emx1-Cre
. Celsr3-defective
corticothalamic axons develop normally, strongly suggesting that those
fibers use guidance mechanisms independent of Celsr3-Celsr3
homophilic interactions. Consistent with this finding, a stall phenotype of
