Multi-functional norrin is a ligand for the LGR4 receptor

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Mammalian leucine-rich repeat-containing G protein-coupled receptors (LGR4, LGR5, LGR6) are crucial for physiological functions.
• These receptors are evolutionarily related to Drosophila DLGR2, activated by burs/pburs, which are involved in morphogenesis.
• While R-spondins are known ligands for LGR4-6, vertebrate orthologs of burs/pburs, like BMP antagonists, were less understood.

Purpose of the Study:

• To identify vertebrate orthologs of Drosophila burs/pburs.
• To investigate the role of norrin as a ligand for LGR4, LGR5, and LGR6 receptors.
• To explore norrin's function in Wnt and BMP signaling pathways and its implications in Norrie disease.

Main Methods:

• Comparative genomics to identify vertebrate orthologs of insect burs/pburs.
• Cell-based assays to examine Wnt signaling activation by norrin through LGR4, LGR5, and LGR6.
• Binding studies to confirm interactions between norrin and LGR4, LGR5, and LGR6.
• Mutagenesis studies on norrin to correlate mutations with signaling defects.

Main Results:

• Norrin was identified as a vertebrate ortholog of insect burs/pburs.
• Norrin specifically stimulated Wnt signaling mediated by LGR4 in mammalian cells, with binding interactions observed for LGR4, LGR5, and LGR6.
• Norrin also activates Wnt signaling via Frizzled4 and acts as a BMP antagonist.
• Mutations in norrin associated with Norrie disease could be classified based on their impact on signaling through these distinct binding proteins.

Conclusions:

• Norrin is a unique ligand that binds to and modulates signaling through LGR4, LGR5, LGR6, and Frizzled4 receptors.
• Norrin plays a significant role in both Wnt and BMP signaling pathways.
• Understanding norrin's interactions provides insights into the molecular mechanisms underlying Norrie disease and related developmental processes.