Neural crest derived boundary cap cells: A source of pericytes to the developing peripheral vasculature

Abstract

In addition to Schwann cells (SC) and sensory neurons, two major components of the peripheral nervous system, the neural crest gives rise to boundary cap cells (BC), transiently located at entry and exit points of all embryonic nerves. By performing BCs fate mapping with mice driving Cre expression under control of BC markers, Krox20/Egr2 and Prss56 we have shown that BC derivatives (BCd) migrate into the nerve roots and nerve terminals of the skin. Whereas in the nerve roots, BC derivatives traced with both markers give rise to SC and sensory neurons, in the skin their fate appeared different. Those deriving from Prss56-expressing BCs correspond to SC, the subpopulation of nerve derived melanocytes and neurogenic stem-like cells. In stark contrast, once arrived under the skin, BC derivatives traced with Krox20 delaminate from nerves and attached to vascular plexus to become mural cells. This “glial vs. vascular” switch occurs between E12.5 and E13.5 and is massive since in the new born skin 30% of pericytes originate from BCs. Transcriptomic comparison of traced cells before and after detachment from nerves led us to identify candidates potentially involved in this mechanism. Among them, Robo3 and its interactors appeared particularly interesting since their expression is restricted to glial cells just before they delaminate from nerves pointing to a role in the detachment. Finally, single cell transcriptomic analysis of BCs before their emigration to the periphery led us to identify clusters of cells with distinct molecular signature supporting their early specification into glial or mural fate. Altogether, our findings suggest a new model for the vasculature development in which glial cells provide first a cocktail of diffusible molecules to shape the vascular plexus into primitive blood vessels, before acting as a major source of mural cells to ensure their maturation into functional blood vessels.