Fig 1: Schematic representation illustrating the key steps during the morphogenesis of the hair bundle and the role of CIB2 in the apical region of the cochlear hair cells AIn the mouse differentiating hair cells, the migration of the kinocilium from the cell centre to the cell periphery between E14.5 and E17.5 initiates a differential growth of the stereocilia; those closest to the kinocilium grow faster and longer forming the tallest stereocilia row. The organization into a highly arranged staircase pattern then takes place and is stabilized during the first postnatal week, when the kinocilium and extra-numerary stereocilia disappear and the proper shape of the hair bundle is refined. The molecular and structural organization is set by P12–P14 at hearing onset and is maintained over time to ensure proper transduction of sound.B, CCIB proteins have been proposed to function as broad regulators of integrin function. (B) At the stereocilia tips, it is yet unknown how lack of CIB2 results in total loss of MET current responses. Possible direct link between CIB2 and the TMC1/2 MET channel complex has been proposed (Giese et al, 2017). (C) Because lack of CIB2 has been shown to alter whirlin and integrin a8 staining at the basolateral regions of the stereocilia, it is likely that this protein is part of a signalling platform, probably through multimers of CIB2, influencing the integrin-mediated essential link between the extracellular matrix and the intracellular cytoskeleton of the hair bundle. It has been suggested that CIB proteins activate integrin (1) (Hynes, 2002; Hager et al, 2008), in a CIB2-mediated “inside-out” signalling (2) process promoting integrin ligand binding, which in turn would affect potential “outside-in” signalling (3) coupling the extracellular matrix (e.g. the a8 subunit) and intracellular responses in the hair bundle (e.g. whirlin and/or FERM proteins). Such a crosstalk might be essential to maintain the shape and stereocilia integrity of the mature functioning hair bundles.