Mesoderm migration in Drosophila is a multi-step process requiring FGF signaling and integrin activity

Abstract

SUMMARYMigration is a complex, dynamic process that has largely been studied using qualitative or static approaches. As technology has improved, we can now take quantitative approaches towards understanding cell migration using in vivo imaging and tracking analyses. In this manner, we have established a four-step model of mesoderm migration during Drosophila gastrulation: (I) mesodermal tube formation, (II) collapse of the mesoderm, (III) dorsal migration and spreading and (IV) monolayer formation. Our data provide evidence that these steps are temporally distinct and that each might require different chemical inputs. To support this, we analyzed the role of fibroblast growth factor (FGF) signaling, in particular the function of two Drosophila FGF ligands, Pyramus and Thisbe, during mesoderm migration. We determined that FGF signaling through both ligands controls movements in the radial direction. Thisbe is required for the initial collapse of the mesoderm onto the ectoderm, whereas both Pyramus and Thisbe are required for monolayer formation. In addition, we uncovered that the GTPase Rap1 regulates radial movement of cells and localization of the beta-integrin subunit, Myospheroid, which is also required for monolayer formation. Our analyses suggest that distinct signals influence particular movements, as we found that FGF signaling is involved in controlling collapse and monolayer formation but not dorsal movement, whereas integrins are required to support monolayer formation only and not earlier movements. Our work demonstrates that complex cell migration is not necessarily a fluid process, but suggests instead that different types of movements are directed by distinct inputs in a stepwise manner.

PDGF-A controls mesoderm cell orientation and radial intercalation duringXenopusgastrulation

“…Following invagination and an epithelial-to-mesechymal transition, a subset of deep mesodermal cells intercalate with more superficial cells that are in contact with the ectoderm (McMahon et al, 2010;McMahon et al, 2008;Murray and Saint, 2007). Radial intercalation of the deep cells depends on signaling by the FGF receptor heartless and its ligands Pyramus and Thisbe, which are all required for normal protrusion formation and intercalation (McMahon et al, 2010;Klingeisen et al, 2009;Murray and Saint, 2007). In our system, different isoforms of PDGF-A regulate both the intercalation of deep mesodermal cells and the directional migration of cells in contact with the BCR (current work and Nagel et al, 2004).…”

Fibroblast growth factor signalling controls successive cell behaviours during mesoderm layer formation in Drosophila

“…Control of mesoderm cell behaviour by FGF It has been proposed that integrin-mediated contacts are responsible for high-affinity ME interactions in Drosophila (McMahon et al, 2010;Murray and Saint, 2007). b1-myospheroid (mys) integrin complexes become concentrated at the ME interface in the late stages of spreading (Leptin et al, 1989;McMahon et al, 2010).…”

“…b1-myospheroid (mys) integrin complexes become concentrated at the ME interface in the late stages of spreading (Leptin et al, 1989;McMahon et al, 2010). It has recently been reported that embryos maternally and zygotically (M/Z) mutant for the mys 1 allele exhibit defects in monolayer formation (McMahon et al, 2010).…”

Synchronous and symmetric migration of Drosophila caudal visceral mesoderm cells requires dual input by two FGF ligands

“…During gastrulation, Htl FGFR-activation by either FGF ligands Pyramus (Pyr) or Thisbe (Ths) supports distinct as well as overlapping activities: Ths controls collapse of the invaginated mesodermal tube; both ligands are required to form a cell monolayer at the culmination of mesoderm spreading; and, following mesoderm spreading, Pyr predominantly supports differentiation of dorsal mesoderm lineages (Klingseisen et al, 2009;McMahon et al, 2010;Michelson et al, 1998). It does not appear that dedicated functions can be ascribed to a ligand for the course of development.…”