Motility and Guidance Signals Control Migration of Muscle Precursors

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Jared Talbot Project summary: Cell migrations are vital to generating a patterned musculature, but only a few of the cues that activate the cell’s motility are known and it remains unclear how muscle progenitors decide to move towards one destination versus another. Here, we will investigate the cues that activate muscle precursor cell motility (Aim 1) and guide the migrating cells (Aim 2) using zebrafish embryos as a model system. In vertebrate embryos, muscle precursor cell migration begins with an epithelial-to-mesenchymal transition (EMT); the cells are then actively guided from somites to new locations in the body, migrating as mesenchymal cell-streams. In mammalian embryos, these cell streams originate from several axial levels to generate over 100 muscles in many body regions. In zebrafish embryos, the homologous migrations are simpler, producing only four muscles: the two limb muscles, the sole neck muscle, and the chest muscle. Paired with other zebrafish strengths, this simplicity makes the zebrafish embryo an excellent model system for understanding muscle precursor cell migrations. We have developed transgenic and mutant lines that enable us to investigate muscle precursor migration in zebrafish embryos. Using these tools, we recently demonstrated that the transcription factors six1 and six4 (collectively termed “six1/4”) are essential for muscle precursor migration in zebrafish. In six1/4 mutants, the muscle precursors fail to undergo EMT and fail to activate the migration-promoting gene met, which encodes a metastasis-inducing receptor protein. Although the six1/4 mutants completely lack precursor migration, this process is only delayed in zebrafish met mutants, suggesting that six1/4 targets additional genes that stimulate motility. In Aim 1A, we will use an unbiased chemical screen to identify new molecules that stimulate muscle precursor motility and guidance. In Aim 1B, we investigate one pathway already suggested by this screen to influence EMT during this migration. In Aim 2, we will investigate how chemokine signals influence this migration. Muscle precursors are thought to be attracted by chemokine (Cxcl12) signaling, which is received by the receptor Cxcr4 and antagonized by the scavenging receptor Ackr3; we propose that the interplay of these two receptors imparts directionality to muscle precursor migration. Chemokine signaling will be altered using genetic mutants and chemical modulators. Cell movement will be analyzed using 3D cell tracking in transgenic embryos. Together these experiments will provide insights into the initiation and guidance of muscle precursor cells, with potential application in other migration-dependent processes like muscle regeneration and metastasis.