AbstractOligodendrocyte precursor cells (OPCs) of the optic nerve are generated in the preoptic area, from where they migrate to colonize it entirely. Sonic hedgehog (Shh) induces the proliferation of these cells as well as influencing their migration, acting through its canonical receptor (Ptc‐1). However, the multiligand receptor megalin (or LRP‐2) is also involved in Shh‐induced OPC proliferation and migration, and thus, we have evaluated the relevance of this interaction. During the stages at which Shh influences OPC development, we found megalin to be selectively expressed by optic nerve astrocytes, whereas Ptc‐1 and Gli1 were found in OPCs. Indeed, this pattern of expression paralleled the rostral–caudal expression of the three Shh‐related molecules during the time course of plp‐dm20+‐OPC colonization. The blockage of megalin partially abolished OPC chemoattraction and fully impaired Shh‐induced proliferation. Using in vitro co‐cultures of dissociated optic nerve cells, we demonstrated that Shh was internalized by astrocytes via megalin, and sufficient Shh was subsequently released to produce the biological effects on OPCs observed in the nerve. Together, these data indicate that at least part of the influence of Shh on OPCs is mediated by megalin during optic nerve development, and that astrocytes expressing megalin transiently capture Shh to present it to OPCs and/or to control the gradient of this molecule during development. © 2012 Wiley Periodicals, Inc.