Musculin and TCF21 coordinate the maintenance of myogenic regulatory factor expression levels during mouse craniofacial development.
The specification of the skeletal muscle lineage during craniofacial development is dependent on the activity of MYF5 and MYOD, two members of the myogenic regulatory factor family. In the absence of MYF5 or MYOD there is not an overt muscle phenotype, whereas in the double Myf5;MyoD knockout branchiomeric myogenic precursors fail to be specified and skeletal muscle is not formed. The transcriptional regulation of Myf5 is controlled by a multitude of regulatory elements acting at different times and anatomical locations, with at least five operating in the branchial arches. By contrast, only two enhancers have been implicated in the regulation of MyoD. In this work, we characterize an enhancer element that drives Myf5 expression in the branchial arches from 9.5 days post-coitum and show that its activity in the context of the entire locus is dependent on two highly conserved E-boxes. These binding sites are required in a subset of Myf5-expressing cells including both progenitors and those which have entered the myogenic pathway. The correct levels of expression of Myf5 and MyoD result from activation by musculin and TCF21 through direct binding to specific enhancers. Consistent with this, we show that in the absence of musculin the timing of activation of Myf5 and MyoD is not affected but the expression levels are significantly reduced. Importantly, normal levels of Myf5 expression are restored at later stages, which might explain the absence of particular muscles in the Msc;Tcf21 double-knockout mice.
Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, UK.
Natalia
N
Moncaut
Joe W
JW
Cross
Christine
C
Siligan
Annette
A
Keith
Kevin
K
Taylor
Peter W J
PW
Rigby
Jaime J
JJ
Carvajal
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D019521:Body Patterning / Q000502:physiology*; D001934:Branchial Region / Q000033:anatomy & histology / Q000196:embryology* / Q000502:physiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000502:physiology*; D009154:Mutation; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C117673:Msc protein, mouse; C491573:Tbx1 protein, mouse; C112923:Tcf21 protein, mouse