Celsr1–3 Cadherins in PCP and Brain Development - Current Topics in Developmental Biology - page 171

In Celsr2 mutant mice ( Celsr2 Dgen/Dgen ), like in off road mutant fishes, the
caudal FBM neuron migration stream is severely truncated. Cells turn lat-
erally, rostral to the abducens nucleus, so that axons do not loop around
nVI and an elongated facial nucleus forms in r4 and r5 instead of r6
( Fig. 7.4C ). When Celsr2 is specifically inactivated in FBM neurons by
crossing with Isl1-Cre mice, a similar phenotype is generated, suggesting
that Celsr2 is required cell autonomously in FBM neurons for their caudal
migration (Qu et al., unpublished). This does not rule out the possibility
that Celsr2 may also be necessary in neuroepithelial cells along the migra-
tion path, as suggested in zebrafish ( Wada et al., 2006 ). The aberrant mi-
gration of FBM neurons in Celsr2 mutant mice is reminiscent of the
situation in birds, which have no facial nerve genu and, intriguingly, lack
a Celsr2 gene ( Formstone, 2010 ). Whether there is a causal link between
the absence of Celsr2 and blunted FBM neuron migration remains an open
question. In zebrafish, Celsr2 , Celsr1a ,and Celsr1b redundantly regulate
FBMN caudal migration. In mouse, double inactivation of Celsr1 and
Celsr2 phenocopies single Celsr2 mutation, with no obvious rostral
migration of FBM neurons, suggesting that Celsr2 is epistatic to Celsr1
( Fig. 7.4C ). It looks as if Celsr2 deficiency hampers or slows down neuro-
nal migration, thus masking the Celsr1 mutant phenotype. Although Celsr3
is required for tangential migration of calretinin-positive interneurons and
radial migration of calbindin-positive interneurons in the forebrain
( Ying et al., 2009 ), its deficiency does not affect the migration of FBM
neurons. It does, however, exacerbate the Celsr2 phenotype: the facial
nucleusisgreatlyreducedinsizein Celsr2 Dgen/Dgen ; Celsr3 ko/ko and
Celsr2 Dgen/Dgen ; Celsr3 Isl1cko as compared to Celsr2 Dgen/Dgen mutant
( Fig. 7.4C and D ). Celsr3 deficiency increases apoptosis in a cell-autonomous
manner. The phenotype of Celsr2 Dgen/Dgen ; Celsr3 ko/ko double mutants is
similar to that of Fzd3 mutants, and other PCP-related genes such as Vangl2
and Wnt5a have been implicated in FBM neuron migration, suggesting that
Celsr1 - 3 regulate neuronal migration along the rostrocaudal axis by
PCP-dependent mechanisms ( Qu et al., 2010; Vivancos et al., 2009 )
( Table 7.1 ). In line with this, normal function of PCP genes such as van
gogh-like 2 ( vangl2 ), fzd3a , celsr2 , prickle1a ,and prickle1b is required for
caudal migration of FBM neurons in fish ( Bingham, Higashijima,
Okamoto, & Chandrasekhar, 2002; Carreira-Barbosa et al., 2003; Jessen
et al., 2002; Mapp, Wanner, Rohrschneider, & Prince, 2010;

Rohrschneider, Elsen, & Prince, 2007; Wada et al., 2006 ).