Biomedical Engineering Reference
In-Depth Information
proteasome. In the presence of Wnts, destruction complex formation
isinhibitedbyDvlthatisactivatedbytheWnt,Fz,andLrp6complex,
therebystabilizingbeta-cateninthataccumulatesinthecytoplasm
to eventually interact with T-cell factor/lymphoid enhancer binding
factor (TCF/LEF) for target gene regulation. The noncanonical
Wnt pathway is independent of beta-catenin and is mediated via
the c-Jun NH2-terminal kinase (JNK) pathway (Wnt/JNK pathway)
or activation of calcium-binding proteins, such as calcineurin, by
intracellular Ca
2+
2+
pathway).
Wnt signaling has spatiotemporally varying roles in heart
development. Cardiac progenitors are derived from the mesoderm
germ layer, and mesoderm formation is dependent on the canonical
Wnt pathway. Mesoderm marker gene expression has not been
detected in Wnt3a -/- mice [41]. Moreover, mesoderm formation
was not observed in beta-catenin knockout mice [42]. These results
suggest that the canonical Wnt pathway tightly regulates mesoderm
formation in early embryos. In mouse ES cells, mesoderm marker
gene expression is reduced by canonical Wnt pathway inhibition
during early phases of differentiation [43] and Wnt3a promotes
cardiac differentiation [44, 45]. From knockout mouse studies,
Wnt2 has been considered to have important roles in mesoderm
commitmentanddiversificationandtoactasapositiveregulator
of cardiac differentiation [46]. In human ES cells, transient Wnt3a
treatment during early phases of differentiation enhances the
formation of embryoid bodies and mesendoderm, leading to
improved cardiomyocyte differentiation [47].
influx(Wnt/Ca
and chickens have shown that ca-
nonicalWntsignalinghasaninhibitoryeffectoncardiacspecifica-
tion[11,48,49].CanonicalWntpathwayactivationintheanterior
mesoderm inhibits early cardiac marker expression (
Previous studies in
Xenopus
and
GATA4) in the cardiac crescent. Wnt1 and Wnt3a expression in ei-
ther the neural or the dorsal neural tubes has been considered to
inhibitcardiacspecificationintheposteriormedialmesoderm.
Paralleling canonical Wnt pathway inhibition of cardiac differentia-
tion, the gene expression of the early transcription factor GATA6 is
negatively regulated by beta-catenin [50], whereas Wnt antagonists
such as Dkk1 and Crescent are expressed in the endoderm underly-
ing the cardiac mesoderm, which induces cardiac differentiation in
theadjacentmesoderm.Furthermore,ectopicexpressionofDkk1
and Crescent in the noncardiac posterior mesoderm induces car-
Nkx2.5
