Dishevelled: In Vivo Roles of a Multifunctional Gene Family During Development - Current Topics in Developmental Biology - page 222

b

-catenin directly regulates Pitx2 gene transcription in pituitary and muscle.
Pitx2 can activate targets including cyclin D2, cyclin D1, and c-Myc and is
required to regulate cell-specific proliferation events. b -Catenin plays a nu-
clear integrating function in Wnt-dependent proliferation events in specific
cell types. With Pitx2 and other transcription factors,

-catenin converts
transcriptional repressors to activators by dismissing HDACs and mediating
sequential recruitment of specific, required coactivator complexes that in-
clude the CBP/p300 complex, the NLI/Ldb/CLIM coactivators of LIM
homeodomain factors, and the TRAP/DRIP/ARC complexes.

b

8. DVL3 MUTANT MICE
Mice homozygous for null alleles of Dvl3 can rarely survive to adult-
hood and are fertile, but, similar to Dvl2 mutants, 80% of Dvl3 homozygotes
in a mixed genetic background and 100% of Dvl3 mutants in a 129/SvEv
inbred background die at birth due to conotruncal heart defects
( Etheridge et al., 2008 ) and display cochlear defects with abnormal orienta-
tion of hair cells. The Dvl3 mutants are the only single Dvl mutants with
cochlear defects, most likely the result of PCP pathway defects. We do
not know the pathway(s) disrupted in conotruncal development in Dvl3
mutants. However, further examination of heart morphogenesis led us to
uncover a mechanism, whereby b -catenin activates a Wnt11-mediated
PCP pathway during heart morphogenesis ( Zhou et al., 2007 ). These studies
suggest that Dvl2 and/or Dvl3 may participate in both canonical and non-
canonical pathways during conotruncal development.

9. DVL DOUBLE MUTANTS: REDUNDANCY AMONG
THE DVL GENES (FIG. 9.1)
Although the analysis of Dvl single mutants uncovered unique pheno-
types for each of the Dvl genes, Dvl double-mutant phenotypes demon-
strated that

there is substantial overlapping and redundant functions

among the three Dvl genes.

10. DVL1/2 DOUBLE MUTANTS

All Dvl1/Dvl2 double homozygotes display completely open neural
tubes and exencephaly, demonstrating an essential role for Dvl genes in neu-
ral tube closure ( Hamblet et al., 2002; Wang, Hamblet, et al., 2006 ). These