Sensory perception in the inner ear relies on the hair bundle, the highly polarized brush of movement detectors that crowns hair cells. We previously showed that, in the mouse cochlea, the edge of the forming bundle is defined by the 'bare zone', a microvilli-free sub-region of apical membrane specified by the Insc-LGN-Gαi protein complex. We now report that LGN and Gαi also occupy the very tip of stereocilia that directly abut the bare zone. We demonstrate that LGN and Gαi are both essential for promoting the elongation and differential identity of stereocilia across rows. Interestingly, we also reveal that total LGN-Gαi protein amounts are actively balanced between the bare zone and stereocilia tips, suggesting that early planar asymmetry of protein enrichment at the bare zone confers adjacent stereocilia their tallest identity. We propose that LGN and Gαi participate in a long-inferred signal that originates outside the bundle to model its staircase-like architecture, a property that is essential for direction sensitivity to mechanical deflection and hearing.

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GPSM2-GNAI Specifies the Tallest Stereocilia and Defines Hair Bundle Row Identity Highlights d GPSM2, GNAI, WHRN, MYO15A, and EPS8 work in the same pathway to shape hair bundles d GPSM2-GNAI-WHRN is a late module added to MYO15A-EPS8 at row 1 stereocilia tips only d GPSM2-GNAI defines the identity of the tallest, first-row stereocilia d Mutant bundles comprise generic stereocilia lacking differential row identity

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In 2011, genome wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer's disease. This finding sparked interest in this member of the sialic acidbinding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer's disease. The allele that protects from Alzheimer's disease acts predominately to increase a CD33 isoform lacking exon 2 at the expense of the prototypic, full-length CD33 that contains exon 2. Since this exon encodes the sialic acid ligand binding domain, the finding that loss of exon 2 was associated with decreased Alzheimer's disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer's disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associated with Alzheimer's disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand binding domain represents a gain of function variant that reduces Alzheimer's disease risk.