title: Cxcl12 evolution--subfunctionalization of a ligand through altered interaction with the chemokine receptor.
abstract: The active migration of primordial germ cells (PGCs) from their site of specification towards their target is a valuable model for investigating directed cell migration within the complex environment of the developing embryo. In several vertebrates, PGC migration is guided by Cxcl12, a member of the chemokine superfamily. Interestingly, two distinct Cxcl12 paralogs are expressed in zebrafish embryos and contribute to the chemotattractive landscape. Although this offers versatility in the use of chemokine signals, it also requires a mechanism through which migrating cells prioritize the relevant cues that they encounter. Here, we show that PGCs respond preferentially to one of the paralogs and define the molecular basis for this biased behavior. We find that a single amino acid exchange switches the relative affinity of the Cxcl12 ligands for one of the duplicated Cxcr4 receptors, thereby determining the functional specialization of each chemokine that elicits a distinct function in a distinct process. This scenario represents an example of protein subfunctionalization--the specialization of two gene copies to perform complementary functions following gene duplication--which in this case is based on receptor-ligand interaction. Such specialization increases the complexity and flexibility of chemokine signaling in controlling concurrent developmental processes.
authors.affiliation: Institute of Cell Biology, Center of Molecular Biology of Inflammation, University of Münster, von-Esmarch-Strasse 56, Münster, Germany.
authors.forename: Bijan
authors.initials: B
authors.lastname: Boldajipour
authors.forename: Maria
authors.initials: M
authors.lastname: Doitsidou
authors.forename: Katsiaryna
authors.initials: K
authors.lastname: Tarbashevich
authors.forename: Cedric
authors.initials: C
authors.lastname: Laguri
authors.forename: Shuizi Rachel
authors.initials: SR
authors.lastname: Yu
authors.forename: Jonas
authors.initials: J
authors.lastname: Ries
authors.forename: Karin
authors.initials: K
authors.lastname: Dumstrei
authors.forename: Sylvia
authors.initials: S
authors.lastname: Thelen
authors.forename: Julia
authors.initials: J
authors.lastname: Dörries
authors.forename: Esther-Maria
authors.initials: EM
authors.lastname: Messerschmidt
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.forename: Petra
authors.initials: P
authors.lastname: Schwille
authors.forename: Michael
authors.initials: M
authors.lastname: Brand
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.forename: Erez
authors.initials: E
authors.lastname: Raz
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D005854:Germ Cells / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D018613:Microscopy, Confocal; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4