Craniofacial Muscles

2 Head Muscle Development
17
normal head muscles (Tajbakhsh et al. 1997 ) . Thus, in the absence of Myf5 , Pax3 is
necessary for the expression of MyoD in the trunk, but not in the head, a fi nding
consistent with the fact that Pax3 is not expressed in head muscle progenitors (Harel
et al. 2009 ) .
The bHLH transcription factors, Capsulin and MyoR, were shown to act as
upstream regulators (presumably repressors) of pharyngeal arch-derived muscle
development. In Capsulin/MyoR double mutants, the masseter, pterygoid, and temporalis
muscles were missing, while distal lower jaw muscles (e.g., anterior digastric
and mylohyoid) were not affected (Lu et al. 2002 ) . In T-box transcription factor
Tbx1 mutants, pharyngeal arch-derived muscles were frequently hypoplastic and
asymmetric, whereas the EOM and tongue muscles were not affected (Kelly et al.
2004 ) . Hence, pharyngeal arch-derived muscles require Tbx1 for robust bilateral
speci fi cation. Head muscle defects in Tbx1 mutants are likely due to an intrinsic
defect in the mesoderm (Dastjerdi et al. 2007 ) , as well as to Tbx1’s indirect function
in the endoderm and ectoderm (Arnold et al. 2006 ) . Indeed, analyses of various
Tbx1 mutant embryos indicated that several fi broblast growth factor (FGF) family
members expressed in these adjacent tissues were down-regulated, demonstrating a
role for Tbx1 and FGF signaling during head muscle development (Hu et al. 2004 ;
Kelly et al. 2004 ; Knight et al. 2008 ; Vitelli et al. 2002 ; von Scheven et al. 2006 ) .
Tbx1 and the bicoid-related homeodomain transcription factor Pitx2 are thought
to be linked to the same genetic pathway in many developmental processes, including
cardiac and craniofacial muscle development (reviewed in Grifone and Kelly
2007 ) . In both mouse and chick, Pitx2 is expressed in the head mesoderm and, subsequently,
in the mesodermal core of PA1 (Dong et al. 2006 ; Shih et al. 2007 ) . In
Pitx2 mutants, the EOM and PA1 muscles of mastication are affected. Pitx2 is
essential for EOM formation. Reducing Pitx2 gene dose results in small rectus muscles,
while eliminating Pitx2 expression completely prevents the formation of all
the EOM (Diehl et al. 2006 ) .
A recent study in mice that addressed the genetic programs promoting myogenesis
in the head muscles revealed distinct requirements for Myf5 and Mrf4 in EOM
and in pharyngeal arch-derived muscles (Sambasivan et al. 2009 ) . Furthermore, this
study suggests that Tbx1 in PM progenitors plays a similar role to that of Pax3 during
somitogenesis. In zebra fi sh, the functions of Myf5 and MyoD during head muscle
formation are non-redundant: in this organism, the homeodomain transcription
factor Six1 seems to play a role in the genetic program regulating development of
subsets of muscles during head myogenesis (Lin et al. 2006, 2009 ) .
In summary, embryological and genetic studies indicate that distinct regulatory
circuits control the formation of head and trunk skeletal muscles. These loss-offunction
studies, combined with fi ndings from lineage tracing studies, highlight the
heterogeneity in head muscle development, such that distinct genetic programs regulate
different groups of muscles within the head. An important open question in the
fi eld is how the aforementioned set of transcription factors expressed in head muscle
progenitors interacts in a hierarchical regulatory network to activate myogenesis in
the head.