Celsr1–3 Cadherins in PCP and Brain Development - Current Topics in Developmental Biology - page 176

the trafficking of Dvl2, and Vangl2 as a well as the subcellular of F-actin
( Trichas et al., 2011 ). Interestingly, when a conserved serine acidic amino
acid-rich domain (SE/D) is deleted from the fish Lyn-Celsr, the membrane
localization of Disheveled is restored ( Carreira-Barbosa et al., 2009 ).
Whereas the extracellular and TM domains are important for the distribu-
tion of Frizzled-Disheveled complexes at the membrane, this process de-
pends critically on the Cter SE/D domain. The ability of Celsr to
regulate epiboly is closely associated with its ability to modulate cell cohesive
property, whereas its ability to interact with the PCP pathway to regulate
convergent extension may not require cell adhesion mediated by the
cadherin repeats.
In the mouse skin, Celsr1 is internalized during epidermal basal progen-
itor division, a process which is crucial for balanced distribution of PCP pro-
teins Fzd6 and Vangl2 in daughter cells and requires a cytoplasmic dileucine
motif. Whereas E-Cadherin is normally not internalized, its fusion with the
Celsr1 cytoplasmic domain induces internalization during mitosis and con-
fers to the chimeric protein the ability to recruit Fzd6 and Vangl2. When the
two leucines (2748-2749) are mutated to alanines, chimeric E-Cad-Celsr1,
like mutated Celsr1, no longer translocates to endosomes ( Devenport et al.,
2011 ).
The Celsr1-3 CTs display much less similarity than their extracellular
and TM regions. As Celsr1 is directly implicated in PCP, and Celsr2-3 in
more distantly related processes, could differences in the C-terminus ac-
count for functional differences? In Drosophila , fmi, fz, and dsh depend on
each other for their membrane localization ( Das et al., 2002 ). Fmi interacts
physically with fz via a region encompassing its HRM and TM domains, and
selectively recruits fz and vang (strabismus) to opposing cell boundaries
( Chen et al., 2008 ). In mice, the membrane localization of Fzd3 and Vangl2
in ependymal cells, Fzd6 and Vangl2 in skin epithelial cells, and Dvl2 and
Vangl2 in the visceral endoderm cells depends on Celsr cadherins
( Devenport & Fuchs, 2008; Tissir et al., 2010; Trichas et al., 2011 ). In
Celsr1 Crsh / Crsh mutant mice, a single amino acid substitution results in
failure of the Celsr1 protein to reach the apical membrane ( Devenport &
Fuchs, 2008; Formstone et al., 2010; Ravni et al., 2009 ). Furthermore, all
six Celsr1 mutations recently identified in human fetuses with
craniorachischisis impair membrane trafficking of Celsr1 in in vitro assays
( Robinson et al., 2011 ). Although not directly useful for definition of
structure-function relationships, this exquisite sensitivity to minor
sequence changes underscores the importance of fmi/Celsr conformation