Proteolytic processing of LRP2 on RPE cells regulates BMP activity to control eye size and refractive error

Abstract

Mutations in LRP2, a transmembrane receptor, cause ocular enlargement and high-myopia. LRP2 is expressed by the RPE and eye ciliary epithelia, binding many extracellular ligands, including Bmp4 and Shh. Signaling mediated by LRP2 is very context-dependent, and how multiple pathways are coordinated is unknown. Transcriptome analyses of ocular tissues revealed that controlled, sustained BMP signaling from the RPE is critical for normal eye growth and emmetropia (proper refraction). Using zebrafish, we demonstrate that BACE sheddase-dependent LRP2 cleavage produces a soluble domain that binds BMP4, inhibiting its signaling. We propose that controlled proteolytic cleavage of LRP2 makes two ligand-binding receptor forms available: a soluble BMP trap, and a membrane-bound RPE signaling facilitator. By modulating LRP2 cleavage, cells can fine-tune and coordinate multiple signaling pathways, as well as growth and turnover of the extracellular matrix, control of which is important to maintain proper eye size. This data supports the concept that LRP2 acts as a homeostasis node that buffers and integrates diverse signaling to regulate emmetropic eye growth.\n\nAuthor SummaryFor proper focusing and normal vision, the axial length of the eye needs to match the refractive power of the lens. This is achieved by fine-tuning multiple signaling pathways to regulate the shape of the eye primarily by remodeling of the sclera, the outermost layer of the eye. This process is termed emmetropization. Emmetropization cues are initiated by visual input, but how signals are transduced from the photoreceptors across the retinal pigment epithelium to the sclera is incompletely understood. Here we show that cleavage of Lrp2, a large receptor expressed on RPE cells in the eye, alters BMP signaling, which contributes to proper eye size control. Dysregulation of BMP signaling by a) absence of Lrp2 in mutant zebrafish or b) overexpression of BMP antagonists from the RPE both cause eye enlargement and myopia. Understanding how regulated cleavage of Lrp2 affects paracrine signaling provides critical insight to emmetropization, raising the possibility for development of therapeutic agents to combat the epidemic incidence of refractive error.