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genes as measured by
in situ
hybridization experiments.
b
arr2 MO effects
can be rescued by expression of
b
arr2
mRNA, by constitutive activation
of the Hh pathway using a dominant negative form of
PKA
mRNA, or
by injecting a MO against su(fu), a Hh function inhibitor. Additional phe-
notypes of
arr2 morphants become apparent later in development, includ-
ing partial cylopia and reduced head size as well as failure of the optic nerve
to form the optic chiasm at 48 hpf. At 72 hpf,
b
arr2 morphants lack cranio-
facial muscle and floor plate development and at 120 hpf they fail to develop
normal cartilage and pectoral fin.
18
Consistent with their positive roles in this cascade, casein kinase CK1
b
a
and GRK2-mediated phosphorylation of Smo facilitates
arr2 interaction
with Smo, preferentially near or at the basal body of the primary cilium.
75
Upon their interaction,
b
arr scaffolds the kinesin motor protein Kif3A,
59
which has been reported to be essential for Hh signaling,
76-78
and all three
proteins translocate into the primary cilium.
23
Inconsistent with their diver-
gent roles during zebrafish development, Kovacs
et al.
23
b
reported that in
mammalian cell cultures, both
arr2 are required for the interac-
tion between Smo with Kif3A, Smo translocation into the primary cilium,
and the subsequent activation of Gli. The reason for this difference between
zebrafish and mammalian cells might be explained by their distinct depen-
dence on the cilium for Hh signaling. While the requirement for cilia and
IFT protein for proper Hh signaling in mice is well documented,
76,77,79,80
such dependence in zebrafish remains uncertain or not fully understood.
A study in zebrafish lacking cilia has suggested a dampening of Hh signal-
ing,
81
while another reported no signaling effect in IFT mutant and mor-
phant fish.
82
Thus, whether and to what extent both
b
arr1 and
b
arr2
would act downstream of the mammalian Smo
in vivo
is still not fully
understood.
Moreover,
kurtz
in
Drosophila
and
b
arr1 and
b
arr2 in vertebrates apparently func-
tion differently regarding Hh signaling. As discussed earlier,
kurtz
has a lim-
iting effect on Hh pathway, whereas vertebrate
b
arr2 is a positive regulator.
This phenomenon probably represents more fundamental differences in the
mechanisms underlying Hh signaling between these species, as Hh signaling
depends on primary cilia only in vertebrates. Interestingly, many inverte-
brates such as flies possess cilia only on sensory neurons. In line with this
notion, it would be fascinating to uncover new roles of
b
arr2 downstream
of the vertebrate Smo. Perhaps Smo can signal through yet unidentified sig-
naling molecules based on the ability of
b
arr2 to recruit secondary scaffolds,
similar to the case for many other GPCRs,
21
even independent of the actions
b
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