Dishevelled: In Vivo Roles of a Multifunctional Gene Family During Development - Current Topics in Developmental Biology - page 221

It is likely that the phenotypes displayed by Dvl1 / mice are mediated by
functions of Dvls in dendritic development ( Rosso, Sussman, Wynshaw-Boris,
& Salinas, 2005 ) and synapse formation ( Ahmad-Annuar et al., 2006 ). Over-
expression of Wnt7b or Dvl increases dendritic branching in cultured hippo-
campal neurons ( Rosso et al., 2005 ), and hippocampal neurons from Dvl1 -
deficient mice display reduced dendritic arborization, an effect mediated by
noncanonical Wnt signaling via activation of Rac and JNK, but not canonical
Wnt signaling. Additionally, cerebellar slices from Wnt7a/Dvl1 double-mutant
mice display defects in neurotransmitter release at mossy fiber-granule cell syn-
apses ( Ahmad-Annuar et al., 2006 ). Dvl1 loss decreased synaptic vesicle
recycling in mossy fibers, while overexpression of Dvl increases the number
of Bassoon clusters. Importantly, Dvls localize to synaptic sites. Thus, Dvl pro-
teins appear tomediate critical behaviors such as social behavior and PPI via PCP
pathway effects on dendritic development and synapse formation.
7. DVL2 MUTANT MICE: CARDIAC, NEURULATION,
AND SKELETAL DEFECTS
Mice homozygous for null alleles of Dvl2 in either inbred 129S6 or
mixed backgrounds can survive to adulthood and are fertile, but they are born
in reduced numbers from heterozygous crosses. Dvl2 homozygotes survive to
term and are born, but 50% die at birth ( Hamblet et al., 2002 ). We have ob-
served patterning defects in Dvl2 mutants: 50% display cardiac defects (the
probable cause of lethality) in the outflow tract, including double outlet right
ventricle and persistent truncus arteriosus. These abnormalities in conotruncal
development are due to a defect in cardiac neural crest development during
outflow tract formation, demonstrated by marker analysis in embryos
( Hamblet et al., 2002; Kioussi et al., 2002 ). In addition to these cardiac
defects, Dvl2 / mice display two other malformations ( Hamblet et al.,
2002 ). Approximately 90% of Dvl2 / mice have vertebral and rib
malformations that affect the proximal as well as the distal parts of the ribs
from defects in somite segmentation. Finally, 2-3% of Dvl2 / embryos
displayed thoracic spina bifida. Thus, Dvl2 is essential for normal cardiac
morphogenesis, somite segmentation, and neural tube closure.
The cardiac defects in Dvl2 mutants may result from a failure in activat-
ing Pitx2 by the Wnt signaling in the Dvl2 mice in the neural crest ( Kioussi
et al., 2002 ). We have obtained genetic and biochemical evidence directly
linking components of the Dvl-Pitx2 pathway in a dosage-dependent fash-
ion to cardiac outflow tract development. Dvl2 acts upstream of Pitx2, and