Celsr1–3 Cadherins in PCP and Brain Development - Current Topics in Developmental Biology - page 168

A B C

Directed fluid flow Aberrant fluid flow

Celsr2
Celsr3
Vangl2

Celsr2 Dgen/Dgen ; Celsr3 f/- ;

WT (P0-P8) WT (adult)

Emx1-Cre (adult)

Figure 7.3 Celsr2 and Celsr3 regulate rotational polarity of ependymal cilia. Represen-
tation of motile cilia anchored to basal bodies (red dots) on the apical surface of
ependymal cells. Cilia develop progressively according to ventral to dorsal, medial to
lateral, and caudal to rostral gradients. During the first postnatal week (P0-P8), basal
feet (green arrowheads) point in different directions (A). In normal animals, they rotate
and adopt a more uniform orientation between P8 and P21, in response to planar cell
polarity signals and hydrodynamic forces. This uniform orientation—also referred to as
rotational polarity—enables cilia to beat in a coordinated manner and to generate a
directed fluid flow (B). In Celsr2 and Celsr3 mutant ependyma (C), basal feet exhibit
divergent orientation and fail to generate a directed fluid flow.

develop in normal numbers and those that develop display abnormalities in
position and planar organization. At the cellular level, basal feet are
misoriented, a rotational polarity defect, and some basal bodies assemble
deep in the cytoplasm. At the tissue level, ciliary tufts from neighboring
cells point aberrantly in divergent directions, generating a translational
polarity defect

þ

2”
structure. They are still able to beat with the same frequency as the
controls. Yet, because of their abnormal orientation, they fail to generate
a robust and directed flow ( Fig. 7.3C ). The membrane localization of
Vangl2 and Fzd3 is disrupted in mutant ependymal cells, providing strong
evidence that Celsr2 and Celsr3 regulate ciliogenesis via PCP signaling.
In accord with this, downregulation of core PCP genes Disheveled1 - 3 ,
and PCP effectors Inturned and Fuzzy affects the orientation of multicilia
in Xenopus ( Park, Haigo, & Wallingford, 2006; Park, Mitchell, Abitua,
Kintner, & Wallingford, 2008 ). Furthermore, ependymal cells with the
“ looptail ” mutation in Vangl2 fail to align their motile cilia in response to
hydrodynamic forces in in vitro assays ( Guirao et al., 2010 ).

( Fig. 7.3C ). Mutant cilia display the typical “9