The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival

Abstract

In mouse embryos, germ cells arise during gastrulation and migrate to the early gonad. First, they emerge from the primitive streak into the region of the endoderm that forms the hindgut. Later in development, a second phase of migration takes place in which they migrate out of the gut to the genital ridges. There, they co-assemble with somatic cells to form the gonad. In vitro studies in the mouse, and genetic studies in other organisms, suggest that at least part of this process is in response to secreted signals from other tissues. Recent genetic evidence in zebrafish has shown that the interaction between stromal cell-derived factor 1 (SDF1) and its G-protein-coupled receptor CXCR4, already known to control many types of normal and pathological cell migrations, is also required for the normal migration of primordial germ cells. We show that in the mouse, germ cell migration and survival requires the SDF1/CXCR4 interaction. First, migrating germ cells express CXCR4, whilst the body wall mesenchyme and genital ridges express the ligand SDF1. Second,the addition of exogenous SDF1 to living embryo cultures causes aberrant germ cell migration from the gut. Third, germ cells in embryos carrying targeted mutations in CXCR4 do not colonize the gonad normally. However, at earlier stages in the hindgut, germ cells are unaffected in CXCR4-/-embryos. Germ cell counts at different stages suggest that SDF1/CXCR4 interaction also mediates germ cell survival. These results show that the SDF1/CXCR4 interaction is specifically required for the colonization of the gonads by primordial germ cells, but not for earlier stages in germ cell migration. This demonstrates a high degree of evolutionary conservation of part of the mechanism, but also an area of evolutionary divergence.

Molecular cloning and embryonic expression of zebrafish PCSK5 co‐orthologues: Functional assessment during lateral line development

“…While the migrating cells express CXCR4, its ligand SDF1 is found in the horizontal myoseptum (David et al, 2002). The same mechanism is reported in mouse germ cell migration and survival (Molyneaux et al, 2003).…”

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

“…This could indicate that the SCs attempted to compensate the loss of SSCs by promoting cell survival. One of the altered SC transcripts was Cxcl12 , which promotes primordial germ‐cell homing to the gonad and the establishment of the spermatogonial stem cell niche (Molyneaux et al ., 2003; Gilbert et al ., 2009; Kanatsu‐Shinohara et al ., 2012). The observed enrichment of the immunological response genes was likely to be a consequence of the increased germ‐cell apoptosis observed in the E2F1 −/− ‐testis.…”

Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse

“…This result suggests that the dispersal of PGCs in the Lhx1 CKO embryo cannot be accounted for by changes in Sl activity in the gut endoderm. The functions of chemokine Sdf1 and the adhesion molecule E-cadherin in the embryonic tissues through which PGCs migrate are crucial for PGCs movement from the gut to the genital ridge (Ara et al, 2003;Molyneaux et al, 2003;Bendel-Stenzel et al, 2000;Gu et al, 2009). However, no discernible change in the expression of either Sdf1 or E-cadherin was detected in the E9.5 Lhx1-CKO embryos (see Supp.…”