Involvement of calcium channels in directed germ cell migration Directed cell migration plays a critical role in tissue patterning and organ morphogenesis of multicellular organisms. One of the more dramatic examples of the importance of direct cell migration in organ morphogenesis is gonad formation. In many organisms the somatic and germline progenitors of the gonad are formed at very distant sites in the embryo and they must find each other in order to coalesce into a functional organ. One of the better understood model systems for gonad morphogenesis is the fruit fly Drosophila. The progenitors of the germline stem cells, the PGCs are formed on the outside surface of the embryo at the blastoderm stage, while the somatic components of the gonad, the gonadial precursor cells (SPGs) arise in the mesoderm mid-way through embryogenesis. To form the embryonic gonad, the PGCs must travel from outside the embryo, through the mid-gut and then migrate through the mesoderm to the SGPs. The migratory path of PGCs is dictated by a series of attractive and repulsive cues. Studies over the past decade in our and other labs has shown that one of the key chemoattractants is the Hedgehog (Hh) ligand. Although Hh is expressed in other cell types in the mesoderm and elsewhere in the ectoderm, the long-distance transmission of this ligand is specifically potentiated in the SGPs by the hmgcr isoprenoid biosynthetic pathway. The activity of the isoprenoid biosynthetic pathway, and thus the distant transmission of the Hh ligand, is gated by restricting expression of hmgcr to the SGPs during mid-embryogenesis. While there are a growing number of instances in which Hh has been shown to function as a guidance clue, it not clear how this classical morphogen or the canonical transcription based signal transduction pathway could induce directed cell movement. Thus, a critical problem is identifying the mechanisms that enable the PGCs to undergo direct migration in response to the Hh ligand. Here we propose studies on two transient potential receptor (TRP) Ca2+ channels, Painless and TRPA1, which have recently been shown to mediate nociception via a Hh dependent mechanism. As Ca2+ influx is known to promote cytoskeleton remodeling, these two channels are excellent candidates for mediating a migratory response to Hh. Preliminary studies indicate that both channels are required for PGC migration, and in the case of Painless we?ve shown that it is expressed specifically in PGCs and that its activity is required in PGCs for proper migration. We propose to further elucidate the role of these calcium channels in directing PGC migration and explore the possibility that they function to link Hh signals emanating from the SGPs to migratory behavior.
Gonad morphogenesis involves recognition, directional migration and sustained association between germ cells and somatic gonadal precursor cells. Elucidating molecular mechanisms underlying these processes is crucial in different contexts including organogenesis, wound healing, and metastasis.
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