Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo
2005
In mammals, Six5, Six4 and Six1 genes are co-expressed
during mouse myogenesis. Six4 and Six5 single knockout (KO)
mice have no developmental defects, while Six1 KO mice die at birth
and show multiple organ developmental defects. We have generated
Six1Six4 double KO mice and show an aggravation of the phenotype
previously reported for the single Six1 KO. Six1Six4 double
KO mice are characterized by severe craniofacial and rib defects, and general
muscle hypoplasia. At the limb bud level, Six1 and Six4
homeogenes control early steps of myogenic cell delamination and migration
from the somite through the control of Pax3 gene expression. Impaired
in their migratory pathway, cells of the somitic ventrolateral dermomyotome
are rerouted, lose their identity and die by apoptosis. At the interlimb
level, epaxial Met expression is abolished, while it is preserved in
Pax3 -deficient embryos. Within the myotome, absence of Six1
and Six4 impairs the expression of the myogenic regulatory factors
myogenin and Myod1, and Mrf4 expression becomes undetectable. Myf5 expression
is correctly initiated but becomes restricted to the caudal region of each
somite. Early syndetomal expression of scleraxis is reduced in the
Six1Six4 embryo, while the myotomal expression of Fgfr4 and Fgf8 but
not Fgf4 and Fgf6 is maintained. These results highlight the different roles
played by Six proteins during skeletal myogenesis.
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