Mural Wnt/β-catenin signaling regulates Lama2 expression to promote neurovascular unit maturation
Saptarshi Biswas, Sanjid Shahriar, Nicholas Giangreco, Panos Arvanitis, Markus Winkler, Nicholas P. Tatonetti, William J. Brunken, Tyler Cutforth, Dritan Agalliu
Abstract
Neurovascular unit and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are crucial for these processes, yet the signaling pathway(s) that regulate their expression remain unknown. Here, we show that mural cells have active Wnt/β-catenin signaling during central nervous system development in mice. Bulk RNA sequencing and validation using postnatal day 10 and 14 wild-type versus adenomatosis polyposis coli downregulated 1 (Apcdd1-/-) mouse retinas revealed that Lama2 mRNA and protein levels are increased in mutant vasculature with higher Wnt/β-catenin signaling. Mural cells are the main source of Lama2, and Wnt/β-catenin activation induces Lama2 expression in mural cells in vitro. Markers of mature astrocytes, including aquaporin 4 (a water channel in astrocyte endfeet) and integrin-α6 (a laminin receptor), are upregulated in Apcdd1-/- retinas with higher Lama2 vBM deposition. Thus, the Wnt/β-catenin pathway regulates Lama2 expression in mural cells to promote neurovascular unit and barrier maturation.