Biomedical Engineering Reference
In-Depth Information
Celsr2
in the adult (
Beall, Boekelheide, & Johnson, 2005; Hadjantonakis,
Formstone, & Little, 1998; Johnson, Patel, & Boekelheide, 2000
).
Polyclonal antibodies against the extra- and intracellular segments of
Celsr1 allowed detection of two forms, full length (p400) and cleaved
(p85 kD), generated by as yet unidentified proteolysis events not involving
the GPS (
Formstone, Moxon, Murdoch, Little, & Mason, 2010
). In the
hindbrain and spinal cord, Celsr1 protein immunoreactivity was detected
in the floor and roof plates, as well as in radial neuroepithelial progenitors,
not only in the apical but also in their basolateral domain, particularly in end-
feet abutting the pial surface (
Formstone et al., 2010
). In the embryonic skin,
Celsr1 is asymmetrically expressed in hair germ cells and in basal layer epi-
dermal cells, a pattern evocative of that of fmi/stan in the Drosophila wing
(
Devenport & Fuchs, 2008
). The cellular localization of Celsr2 and Celsr3
could not be investigated thus far due to lack of antibodies suitable in
immunohistochemistry.
2. CELSR1: A MAJOR PLAYER IN VERTEBRATE PCP
Two
Celsr1
mutant alleles,
Crash
(
Celsr1
Crsh
) and
Spin Cycle
(
Celsr1
Scy
),
were identified in an ENU screen (
Curtin et al., 2003
). In
Celsr1
Crsh
, a G-to-
A mutation at nucleotide 3126 results in an aspartate-to-glycine substitution
in codon 1040, within the eighth cadherin repeat. In
Celsr1
Scy
, a T-to-A
point mutation at nucleotide 3337 results in an asparagine-to-lysine substi-
tution in codon 1110, in a region connecting cadherin repeats. Heterozy-
gous animals show abnormal head-shaking behavior. Both heterozygous
and homozygous mice have defective organization of stereocilia bundles
in inner ear hair cells. Normally, the apical surface of each cochlear hair cell
is decorated with actin-filled stereocilia forming a “V” centered on a micro-
tubular kinocilium, with all “Vs” pointing to the external aspect of the co-
chlear canal. In
Celsr
Crsh
and
Celsr1
Scy
mutant mice, this typical organization
is altered. Stereociliary bundles are randomly oriented, some displaying up to
180
rotation relative to the normal orientation (
Curtin et al., 2003
). The
precise orientation of hair bundles in the cochlea is a classical hallmark of
PCP and parallels the polarized distribution of core PCP proteins such as
Fzd3, Fzd6, Vangl2, and Prickle2 (
Deans et al., 2007; Montcouquiol
et al., 2006; Wang, Guo, & Nathans, 2006
). PCP proteins localize
asymmetrically to one edge of the apical cortex of the cells by
mechanisms involving selective targeting and protein stabilization and
degradation. Intriguingly,
studies of
the distribution of PCP proteins
