Abstract
The paired-box homeodomain transcription factor Pax3 is a key regulator of the nervous system, neural crest and skeletal muscle development. Despite the important role of this transcription factor, very few direct target genes have been characterized. We show that Itm2a, which encodes a type 2 transmembrane protein, is a direct Pax3 target in vivo, by combining genetic approaches and in vivo chromatin immunoprecipitation assays. We have generated a conditional mutant allele for Itm2a, which is an imprinted gene, by flanking exons 2–4 with loxP sites and inserting an IRESnLacZ reporter in the 3′ UTR of the gene. The LacZ reporter reproduces the expression profile of Itm2a, and allowed us to further characterize its expression at sites of myogenesis, in the dermomyotome and myotome of somites, and in limb buds, in the mouse embryo. We further show that Itm2a is not only expressed in adult muscle fibres but also in the satellite cells responsible for regeneration. Itm2a mutant mice are viable and fertile with no overt phenotype during skeletal muscle formation or regeneration. Potential compensatory mechanisms are discussed.
Highlights
Pax genes, which encode paired domain transcription factors, play key roles in tissue specification and organogenesis during embryonic development [1]
Development The gene encoding the transmembrane protein Itm2a emerged as a potential Pax3 target in myogenic progenitors in the mouse embryo [22]
We conclude that Itm2a marks satellite cells and myonuclei of most fibers but is dispensable for adult myogenesis. In this investigation of the role of Itm2a during skeletal muscle formation in vivo, we demonstrate that the Pax3 binding site in the first intron of the Itm2a gene [19] binds Pax3 in vivo, as demonstrated by chromatin immunoprecipitation (ChIP) experiments with embryonic extracts
Summary
Pax genes, which encode paired domain transcription factors, play key roles in tissue specification and organogenesis during embryonic development [1]. Pax3-positive cells, that have not yet entered the myogenic program, migrate into the limb bud where they provide the progenitor cell pool for skeletal myogenesis. The central domain of the dermomyotome loses its epithelial structure and Pax3/Pax7-positive myogenic progenitors enter the underlying muscle mass of the myotome, which later expands and segments to give rise to the muscles of the trunk. In the Pax3/Pax double mutant, these cells fail to enter the myogenic program, and many of them die [2] This population is the source of postnatal myogenic progenitors, known as satellite cells because of their characteristic position under the basal lamina of the muscle fiber [3,4]. Pax7/3 are down-regulated prior to the onset of differentiation, or remain expressed in cells that reconstitute the satellite cell pool
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