![]() ![]() In the zebra fish embryo, the slow program is under the control of Hedgehog signaling from the notochord and floor plate. Muscles are composed of multinucleated muscle fibers with different contractile and physiological properties, which result from specific slow or fast gene expression programs in the differentiated muscle cells. Our findings provide an example of how Pbx homeodomain proteins act in a balance with other transcription factors to regulate subsets of a cellular differentiation program. ![]() Thus, our findings reveal that subsets of the fast muscle program are differentially regulated by Pbx and Prdm1a. However, other fast muscle genes require Pbx but are not regulated by Prdm1a. We find that the levels of expression of certain fast muscle genes are increased or approximately wild type in pbx2/4-MO prdm1a-/- embryos, suggesting that Pbx activity normally counters the repressive action of Prdm1a for a subset of the fast muscle program. To determine whether Pbx and Prdm1a have opposing activities on a common set of genes, we used RNA-seq analysis to globally assess gene expression in zebrafish embryos with single- and double-losses-of-function for Pbx and Prdm1a. The prdm1a mutant phenotype, early and increased fast muscle differentiation, is the opposite of the Pbx-null phenotype, delayed and reduced fast muscle differentiation. Here we have investigated the interactions of Pbx with another muscle fiber-type regulator, Prdm1a, a SET-domain DNA-binding factor that directly represses mylpfa expression and fast muscle differentiation. We have previously shown that Pbx proteins bind with Myod on the promoter of the zebrafish fast muscle gene mylpfa and that Pbx proteins are required for Myod to activate mylpfa expression and the fast-twitch muscle-specific differentiation program in zebrafish embryos. We hypothesize that Pbx homeodomain proteins direct Myod to a subset of its transcriptional targets, in particular fast-twitch muscle differentiation genes, thereby regulating the competence of muscle precursor cells to differentiate. The basic helix-loop-helix factor Myod initiates skeletal muscle differentiation by directly and sequentially activating sets of muscle differentiation genes, including those encoding muscle contractile proteins. Taken together, these findings provide new insights into the molecular basis of vertebrate muscle fiber-type specification, and underscore Blimp1 as the central determinant of this process. Finally, we show that zebrafish Blimp1 can repress the expression of fast muscle-specific myosin light chain, mylz2, through direct binding near the promoter of this gene, indicating that an important function of the transcriptional activity of Blimp1 in slow muscle development is the suppression of fast muscle-specific gene expression. ![]() Furthermore, we provide evidence that mammalian Blimp1 can recapitulate the slow myogenic program in zebrafish, suggesting that zebrafish Blimp1 can recognize the same consensus DNA sequence that is bound by the mammalian protein. We demonstrate that the competence of somitic myoblasts to commit to the slow lineage in response to Blimp1 changes as a function of developmental time. In slow myoblasts, expression of the Blimp1 protein is transient, and precedes the expression of slow muscle-specific differentiation genes. Here, we have investigated the mechanism by which Blimp1 programs myoblasts to adopt the slow-twitch fiber fate. We have previously shown that within the somites of the zebrafish embryo, the activity of the zinc finger and SET domain-containing transcriptional regulator Blimp1 is essential for the specification of slow muscle fibers. During myogenesis, how muscle precursors are induced to mature into distinct slow- or fast-twitch fiber-types is inadequately understood. Skeletal muscles of vertebrates are typically composed of slow- and fast-twitch fibers that differ in their morphology, gene expression profiles, contraction speeds, metabolic properties and patterns of innervation. ![]()
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