BMP signalling attenuates intercellular adhesion to drive mesenchyme migration during fin fold morphogenesis

Abstract

The development of the vertebrate limb bud is a multifactorial process involving the coordinated activity of diverse signalling pathways and cell types. BMP signalling has been consistently shown to play an integral role during the patterning of mouse and chick limbs. However, the molecular mechanisms and cellular processes underlying its contribution to limb development are poorly understood. Using zebrafish embryos, we demonstrate a novel role of BMPs in driving median fin fold morphogenesis, an evolutionary related structure. Our findings indicated that a graded BMP signal is established in the emerging fin fold along the proximo-distal axis, with the fin mesenchymal cells being identified as the primary target of the signalling cue. Pharmacological and genetic ablation of BMP signalling in the fin fold inhibited the normal migration of the mesenchymal cells into the fin fold. The observed inhibition of migration was accompanied by the elongation in mesenchymal cell shape, which hinted at the possibility of altered physical forces acting on the cell population. We observed that loss of BMP signalling led to the cellular re-distribution and altered membrane dynamics of N-cadherin in the fin mesenchymal cells, which manifested as an increase in homotypic cell adhesion. This change in cell-adhesion serves as the mechanistic basis for the observed defect in migration. Furthermore, inability to detach due to loss of BMP signalling occurs independently of sphingosine-1-phosphate signalling that generates a gradient of mesenchyme adhesion to the underlying matrix. Overall, this study highlights the cellular and molecular mechanism underlying the role of BMPs in coordinating early fin bud morphogenesis.