Celsr1–3 Cadherins in PCP and Brain Development - Current Topics in Developmental Biology - page 175

By contrast, C-terminally deleted fmi ( D CFmi) retains the ability to mediate
homophilic binding in vitro and rescues the tiling phenotype, but not
the dendritic overgrowth or fly viability, pointing to a key role of the
C-terminus. Thus, a dual molecular function of Fmi plays pivotal roles in
dendrite morphogenesis. In the initial growing phase, Fmi might function
as a receptor for an unidentified ligand, and this hypothetical heterophilic
interaction would be responsible for limiting branch elongation. At a later
stage, homophilic Fmi-binding at dendro-dendritic interfaces would elicit
avoidance between dendritic terminals from opposing neurons ( Kimura
et al., 2006 ). Likewise, studies in worms, flies, and mice show that the
function of fmi/Celsr in axon guidance does not rely only on its ability
to mediate homophilic binding of cadherin repeats but also requires inter-
actions of the C-terminus with unknown molecules ( Steimel et al., 2010;
Steinel & Whitington, 2009; Zhou et al., 2008 ).
The concept of distinct roles of the extra- and intracellular domains of
fmi/Celsr is supported by mutation analysis in vertebrates. In rodents, Celsr2
and Celsr3 have opposing roles on dendrites in brain slice in culture,
with Celsr2 promoting and Celsr3 restricting dendrite growth ( Shima
et al., 2004, 2007 ). Studies of chimeric constructs in which the
ectodomains of Celsr2 and Celsr3 are swapped show that, whereas
homophilic interactions (Celsr2-Celsr2 and Celsr3-Celsr3) are important,
the transmembrane domains and C-terminus determine the dendrite
enhancing or suppressing action. Celsr2 and Celsr3 have different effects
on calcium release and activate, respectively, CamKII and Calcineurin
signaling, and an amino acid change (R2413H) in the first intracellular
loop is crucial to these distinct functions.
Another evidence for the importance of the C-terminus comes from a
study in zebrafish ( Carreira-Barbosa et al., 2009 ). Injection of a C-terminally
truncated form of Celsr ( D C-celsr; lacking 6 TM and tail) in wild-type em-
bryos generates epiboly defects. This is accompanied by sequestration of
D C-Celsr in the Golgi, where the protein behaves as a dominant negative,
dimerizing with and precluding trafficking of the wild-type protein. Dimer-
ization is thought to involve a conserved arginine-rich sequence N-terminal
to the first cadherin repeat. Injection of the CT of Celsr2 fused to the mem-
brane localization signal from the Lyn tyrosine kinase (Lyn-celsr) generates
convergent extension defects without affecting epiboly. Lyn-celsr perturbs
the Frizzled-induced membrane localization of Disheveled and thus PCP
signaling. In mammals, knock-in of the mouse Celsr1 C-tail fused to mem-
brane localization signal Lyn in the ubiquitous Rosa26 locus also perturbs