Control of receptor internalization, signaling level, and precise arrival at the target in guided cell migration

Activation of the chemokine receptor CXCR4 by SDF1 controls a variety of biological processes in development, immune response, and disease [1-5]. The carboxyl-terminal region of CXCR4 is subject to phosphorylation that allows binding of regulatory proteins [5]; this results in downregulation of CXCR4 signaling and receptor internalization [6]. Notably, truncations of this part of CXCR4 have been implicated in WHIM syndrome, a dominantly inherited immunodeficiency disorder [7, 8]. Despite its importance in receptor signaling and the clinical relevance of its regulation, the precise function of regulating signaling level and internalization in controlling cell behavior is not known. Whereas a number of in vitro studies suggested that the carboxyl terminus of CXCR4 positively regulates chemotaxis (e.g., [9]), others reached the opposite conclusion [8, 10, 11]. These conflicting results highlight the importance of investigating this process under physiological conditions in the live animal. In this study, we demonstrate the significance of internalization and of controlling receptor signaling level for SDF-1-guided migration. We found that whereas internalization and the control over signaling intensity are dispensable for cell motility and directional sensing, they are essential for fine-tuning of migration in vivo, allowing precise arrival of zebrafish PGCs at their target, the region where the gonad develops.