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heart and skeletal muscles, and was therefore designated as striated muscle (SM)
UNC-45 (Price et al.
2002
). The two isoforms share 50-55 % sequence identity in
both human and mouse. There is > 90 % sequence identity among similar isoforms
between these species. When compared with
C. elegans
UNC-45, both isoforms
show 30-40% identity with the worm protein. In eight-day old mouse embryo,
UNC-45b is predominantly expressed in the contractile heart and is hardly found
in other organs; whereas UNC-45a is diffusely expressed and later concentrates in
regions of intense development such as the branchial arches and forelimb bud (Price
et al.
2002
).
Studies on
Danio rerio
(zebrafish) confirmed that UNC-45a has important func-
tion in pharyngeal arch and aortic arch development and UNC-45a is involved in the
generation of arteriovenous malformation (AVM) (Anderson et al.
2008
). Knock-
down of UNC-45b in zebrafish by morpholino-oligonucleotide caused myofibril
disassembly in the sarcomeres of the trunk muscle and the ventral displacement of
jaw cartilages, thus demonstrating that the protein is required for skeletal, cranial
and cardiac muscle contraction (Wohlgemuth et al.
2007
). Therefore, UNC-45b is
necessary for zebrafish motility and it is also essential for morphogenesis and func-
tion of the developing heart and jaw. Overexpression of
D. rerio
UNC-45b mim-
icked results of similar experiments in
C. elegans
as transgenic zebrafish embryos
had defective myofilament assembly in skeletal muscles (Bernick et al.
2010
). The
defect by UNC-45b overexpression was shown to depend on the UCS domain but
not the TPR domain since deletion of the UCS domain revoked myofibril disorga-
nization by UNC-45b overexpression and deletion of the TPR domain had no effect
(Bernick et al.
2010
). Further studies on zebrafish revealed that the central region
of UNC-45b mediated Z line association and interacted with Apo2a (the cytidine
deaminase Apobec 2a) (Etard et al.
2008
,
2010
). The interaction between UNC-45b
and Apo2a is necessary for integrity of the myosepta and myofiber attachment in
zebrafish, which is Hsp90-independent (Etard et al.
2010
). The
apo2
mutant em-
bryos share similar dystrophic muscle phenotypes with
unc45b
mutants but not with
hsp90α
mutants as
hsp90α
mutant had normal myosepta structure and a beating
heart (Etard et al.
2010
). Missense mutation of
Xenopus tropicalis
UNC-45b caused
skeletal muscle myofibril disruption, paralysis and heart beat problem, suggest-
ing that UNC-45b participates in the Z-body maturation (Geach and Zimmerman
2010
). A major implication of these studies is that loss of function of UNC-45 may
lead to defective muscle formation and thus myopathies (Etard et al.
2008
,
2010
;
Geach and Zimmerman
2010
).
In C2C12 myogenic cells, only UNC-45a mRNA is detected in proliferating
myoblasts, with the level decreasing as the cells progress to form myotubes (Price
et al.
2002
). In contrast, UNC-45b mRNA is detected only after the cells start fus-
ing, peaking in young myotubes and dropping off as the myotubes age (Price et al.
2002
). These observations in both mouse embryo and C2C12 myoblasts implicate
stage-specific expression and functions of the UNC-45 isoforms in embryogenesis
and muscle differentiation. The UNC-45a isoform may be involved in cell divi-
sion and related cytoskeletal formation while the UNC-45b isoform may be re-
lated to striated muscle differentiation and myofibril formation. In fact, in C2C12
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