Stereociliary localization and function of the tip-link protein PCDH15-CD2 are regulated by the PDZ-scaffold NHERF-1

In mouse auditory hair cells, CD2–NHERF-1 binding is required for correct CD2 levels and stereociliary localization, and its loss causes high-frequency hearing loss and adult degeneration.

• Why it matters: Hair-bundle proteins must be delivered to precise stereocilia sub-compartments and maintained, but how tip-link components like PCDH15 are regulated spatiotemporally is unclear.
• What they did: In vitro biochemical assays showed NHERF-1/2 PDZ scaffolds directly bind the CD2 isoform; mapping implicated NHERF-1 PDZ1 and CD2 PBM, with phosphorylation regulating the interaction. Nherf1 knockout and Pcdh15-CD2 knock-in mice tested in vivo requirements.
• The result: Disrupting the interaction largely spared early bundle morphogenesis and MET function, yet produced high-frequency hearing loss and degeneration of the shortest stereociliary row in adult mice, supporting a targetable mechanism for hair-bundle repair.

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