Biomedical Engineering Reference
In-Depth Information
shown to be required for convergence and extension as well as newly iden-
tified PCP-dependent processes such as neuronal migration and axon guid-
ance. While effects of inhibition of JNKs during cochlear development have
not been examined,
in vitro
inhibition of JNKs during hair cell regeneration
in the chicken utricle has been shown to lead to an inhibition of uniform
bundle orientation (
Warchol & Montcouquiol, 2010
).
3.7. The fat/dachsous pathway
There is an ongoing debate as to the degree of interaction between the core
fz-Vangl2 pathway and the fat/dachsous signaling pathway in PCP. In
Drosophila
, fat/dachsous signaling involves two protocadherins, fat and
dachsous, and a transmembrane protein four-jointed, which was initially
characterized as a PCP protein (
Zeidler, Perrimon, & Strutt, 1999
).
Four-jointed, a Golgi protein, acts to phosphorylate both fat and dachsous.
Fat suppresses transcription of four-jointed, while dachsous in turn represses
fat activity (
Simons & Mlodzik, 2008
). While still not completely clear, fat/
dachsous signaling appears to work in parallel with the core PCP pathway.
Recent work in mammals has demonstrated roles for the murine homo-
logs of these three genes that are consistent with a role in PCP signaling
(
Rock,Schrauth,&Gessler,2005
). A single homolog for four-jointed,
Fjx1
, has been identified, and a mutant mouse has been generated, although
no PCP phenotype was observed in the ear or elsewhere (
Probst, Rock,
Gessler, Vortkamp, & Puschel, 2007
). In contrast, clear PCP phenotypes have
been observed in one of the murine
Fat
mutants. Four mouse homologs of
fat
have been identified,
Fat1
-
4
with
Fat4
most closely related structurally
to
Drosophila fat
(
Saburi, Hester, Goodrich, & McNeill, 2012
). Targeted
deletion of
Fat4
leads to PCP defects in mutant mice including disrupted neu-
ral tube closure, shortened cochlea ducts, and disrupted hair bundles, although
the latter two defects are relatively mild (
Saburi et al., 2008
). Expression of
Fjx1
was increased in
Fat4
mutants, indicating a conserved role for
Fat
in reg-
ulation of
Fjx1
in vertebrates.
Fat4
was also shown to interact genetically with
Fjx1
and
Vangl2
in kidney, yet localization of Vangl2 in the kidney in
Fat4
mutants was not disrupted, consistent with parallel pathways. Similar studies
in the inner ear have not been conducted as yet.
Similarly, targeted disruption of
Dchs1
, the most closely related mamma-
lian homolog of
dachsous
, leads to similarly mild cochlear PCP defects (
Mao
et al., 2011
). Cochlear PCP defects were not exacerbated in
Dchs1
/
Fat4
dou-
ble mutants, suggesting disruption of a common pathway. As is the case in
Drosophila
, the precise interactions between Fjx1-dachsous-fat proteins and
