Celsr1–3 Cadherins in PCP and Brain Development - Current Topics in Developmental Biology - page 174

axons at intermediate target cells was reported for fmi-defective sensory
neurons in flies ( Steinel & Whitington, 2009 ). These phenotypes can be
rescued by fmi constructs that lack most of the extracellular domains,
indicating that the advance of sensory axons in flies does not depend on
fmi-fmi homophilic interactions ( Steinel & Whitington, 2009 ). Contrary
to corticothalamic axons, corticospinal axons do not develop in
Celsr3 Emx1cKO , suggesting that Celsr3 mediates homophilic interactions
between corticospinal growth cones and guidepost cells. In support of
this, in the fly visual system, fmi mediates interactions between the
growth cones of photoreceptor axons and their targets in the medulla
( Hakeda-Suzuki et al., 2011 ). Like in flies and mammals, FMI-1, the sole
C. elegans fmi/stan ortholog, enables navigation of both pioneer
and follower axons in the worm's ventral nerve cord. Rescue of FMI-
1 mutant phenotype with different portions of FMI-1 revealed that the
C- and N-termini are required for guidance of pioneer and follower
axons, respectively ( Steimel et al., 2010 ). Taken together, these data
show that flamingo and its mammalian ortholog Celsr3 are major players
in axon guidance and that their mechanisms of action are context
dependent and involve both homophilic and heterophilic interactions.
5.1. Motifs of Celsr important for their functions
As mentioned in the introduction, Celsr proteins contain a large extracellu-
lar N-terminus with nine cadherin repeats, EGF-like and laminin G-like
motifs, a HRM, a G-proteolysis site, followed with seven transmembrane
domains and a variable intracellular C-terminal tail. Although the functional
relevance of these motifs remains poorly understood, some studies have rev-
ealed a few hints. In Drosophila S2 cells—which have no self aggregation
properties—expression of full-length fmi induces cell aggregation, whereas
expression of a form lacking most of the ectodomain does not, showing that
the extracellular domain indeed promotes homophilic cell adhesion ( Usui
et al., 1999 ). Expression of mutant forms of mammalian Celsr2 in S2 cells
assigned adhesive properties to the cadherin repeats ( Shima et al., 2004 ).
Dendritic overgrowth and tiling defects of fmi mutants as well as fly vi-
ability can be rescued by expression of full-length fmi, although the rescue
can be ascribed to two different functions of the protein. In transgenic rescue
experiments, D Nfmi—lacking all extracellular domains except the HRM—
can rescue the dendrite overgrowth but not the tiling phenotype. Unlike
full-length fmi, D Nfmi does not promote S2 cell aggregation in vitro .