(B) Whole mount in situ hybridization (WISH) photomicrograph of cxcl12a along the horizontal myoseptum in the trunk and tail of an approximately 32 hpf embryo. (A) Schematic showing migration of the PLLp (green and red) along a stripe of cxcl12a expression (blue). The Polarized Expression of Cxcr4b and Cxcr7b in the PLLp Determines Unidirectional Migration of the PLLp Along a Relatively Uniform Stripe of cxcl12a Expression.
However, the relative size of the cxcr7b expression domain waxes and wanes, as a large fraction of cxcr7b-expressing cells in the trailing part of the PLLp is lost every time a neuromast is deposited by the migrating PLLp ( Aman et al., 2011).įIGURE 15.6.
The domain of cxcr4b expression is relatively constant in the PLLp during a deposition cycle. Although transcripts for cxcr4b are in a leading zone, they overlap a little with cxcr7b in the trailing zone, where Cxcr4b protein is also likely to be expressed. The direction of PLLp migration is, instead, determined by the polarized expression of two chemokine receptors, Cxcr4b and Cxcr7b, in the leading zone and in the trailing zone of the PLLp, respectively ( Figure 15.6) ( Dambly-Chaudiere et al., 2007 Valentin et al., 2007). In fact, in fused somite mutant embryos, in which the stripe of cxcl12a ends prematurely, the PLLp sometimes makes a “U”-turn at the end of the cxcl12a path and begins to migrate in the opposite direction, illustrating that there is no inherent directional information in the stripe of cxcl12a expression ( Haas and Gilmour, 2006). Although the expression of cxcl12a along the horizontal myoseptum determines the path followed by the migrating PLLp, it does not determine the direction of migration. The PLLp migrates from the ear to the tip of the tail following a path defined by the chemokine (C-X-C motif) ligand 12a (Cxcl12a), also known as Stromal cell derived factor 1a (Sdf1a), expressed by muscle pioneer cells along the horizontal myoseptum ( David et al., 2002 Li et al., 2004) ( Figure 15.6). If Cxcr7b acts as an Sdf1 sink in the trailing region of the primordium as well, the regionally distinct combinations of cxcr4b and cxcr7b expression in the primordium might enable individual cells to detect a Sdf1 gradient necessary for directed migration. Therefore, Cxcr7b modulates the amount of Sdf1 available to bind to Cxcr4b, which enables PGCs to detect an Sdf1 gradient guiding the cells toward the developing gonads. A beautiful study of the roles of chemokine signaling in primordial germ cell (PGC) migration in zebrafish discovered that Cxcr7b can also function as an Sdf1 sink without activating an intracellular signaling cascade. However, given that neither receptor is dispensable, the two chemokine receptors either bind Sdf1 with different affinities, or they elicit distinct intracellular responses upon ligand binding. This finding initially seemed puzzling, since both receptors bind to Sdf1. Both receptors are necessary for directed migration, as loss of either one disrupts migration. This hypothesis is supported by the finding that the two chemokine receptors cxcr4b and cxcr7b are expressed in opposing poles of the primordium ( Figure 227.3c, d).
This finding led to the hypothesis that Sdf1 protein is not expressed as a gradient along the horizontal myoseptum, but rather that the primordium itself is polarized or is able to create an Sdf1 gradient within the primordium. However, in some zebrafish mutants the primordium turns around on itself midway down the trunk and migrates back toward the head. Initially it was thought that Sdf1 was expressed in a gradient that guides the primordium to the tail tip. The two Sdf1 receptors Cxcr4b and Cxcr7b, on the other hand, are expressed in complementary regions of the primordium ( Figure 227.3b, c ). The chemokine ligand Sdf1 is expressed in cells along the horizontal myoseptum, prefiguring the track on which the primordium will migrate ( Figure 227.3b). Several studies have demonstrated that chemokine signaling is the major guidance system employed by the primordium. Nevertheless, the primordium does not stray on its way, but migrates straight along the horizontal myoseptum (a connective tissue along the midline of the trunk) toward the tail tip. Guided primordium migration is a fascinating process, as the primordium migrates along the embryonic axis, thereby encountering many different positional cues. Tatjana Piotrowski, in Handbook of Cell Signaling (Second Edition), 2010 Chemokine Signaling Guides the Migrating Primordium
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