Norrin, also known as the Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein, is a secreted retinal growth factor with angiogenic and neuroprotective properties. Mutations in the NPD gene, which encodes the Norrin protein, are associated with Norrie disease, familial exudative vitreoretinopathy (FEVR), retinopathy of prematurity (ROP), and other retinal hypovascularization diseases1,2. Norrin has a weak homology with TGF-β, but no significant sequence homology with Wnt proteins. The crystal structure of Norrin revealed a dimeric complex of Norrin that folds more like TGF-β than Wnt3. However, Norrin does not activate the TGF-β pathway. Instead, despite its structure being distinct from that of Wnt proteins, Norrin functions predominantly through the activation of the canonical Wnt/β-catenin signaling pathway. Frizzled 4 (Fz4), but not other Frizzled family members, serves as the primary receptor for Norrin on the cell surface. The Norrin-Fz4 interaction is essential for Norrin signaling and function, as both NPD mutations and FZD4 mutations are associated with FEVR. How Norrin activates the Wnt/β-catenin signaling pathway through its interaction with Fz4 remains enigmatic.

The 133-residue Norrin forms a covalent homodimer, with three pairs of intermolecular disulfide bonds, in addition to four pairs of intramolecular disulfide bonds in each Norrin subunit3. This structure does not immediately explain that Norrin can specifically recognize Fz4, which is also a receptor for canonical Wnt proteins (e.g., Wnt8)4, and activate the canonical Wnt/β-catenin signaling pathway inside the cell. Frizzled proteins, along with smoothened, a hedgehog regulator, form the class F GPCR family. This family of receptors only weakly activates G-protein or arrestin pathways, the canonical signaling mechanisms downstream of the other GPCR classes. Like other Frizzled proteins, Fz4 contains a ∼120-residue N-terminal extracellular cysteine-rich domain (CRD) followed by the 7-helix transmembrane domain. Due to the technical difficulties generating soluble Norrin and Wnt proteins, the only complex structure available for the Frizzled family is that of the Wnt8/Fz8-CRD complex5. Structural information regarding Norrin-Fz4 interaction would provide key insights into many important aspects of cell signaling.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD