Auditory collusion and a coupled couple of outer hair cells.

The discrepancies between measured frequency responses of the basilar membrane in the inner ear and the frequency tuning found in psychophysical experiments led to Bekesy's idea of lateral inhibition in the auditory nervous system. We now know that basilar membrane tuning can account for neural tuning, and that sharpening of the passive travelling wave depends on the mechanical activity of outer hair cells (OHCs)3, but the mechanism by which OHCs enhance tuning remains unclear. OHCs generate voltage-dependent length changes at acoustic rates, which deform the cochlear partition. Here we use an electrical correlate of OHC mechanical activity, the motility-related gating current, to investigate mechano-electrical interactions among adjacent OHCs. We show that the motility caused by voltage stimulation of one cell in a group evokes gating currents in adjacent OHCs. The resulting polarization in adjacent cells is opposite to that within the stimulated cell, which may be indicative of lateral inhibition. Also such interactions promote distortion and suppression in the electrical and, consequently, the mechanical activity of OHCs. Lateral interactions may provide a basis for enhanced frequency selectivity in the basilar membrane of mammals.     

Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein.

The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act as molecular switches in signalling pathways that regulate cytoskeletal architecture, gene expression and progression of the cell cycle. Cdc42 and Rac transmit many signals through GTP-dependent binding to effector proteins containing a Cdc42/Rac-interactive-binding (CRIB) motif. One such effector, the Wiskott-Aldrich syndrome protein (WASP), is postulated to link activation of Cdc42 directly to the rearrangement of actin. Human mutations in WASP cause severe defects in haematopoletic cell function, leading to clinical symptoms of thrombocytopenia, immunodeficiency and eczema. Here we report the solution structure of a complex between activated Cdc42 and a minimal GTPase-binding domain (GBD) from WASP. An extended amino-terminal GBD peptide that includes the CRIB motif contacts the switch I, beta2 and alpha5 regions of Cdc42. A carboxy-terminal beta-hairpin and alpha-helix pack against switch II. The Phe-X-His-X2-His portion of the CRIB motif and the alpha-helix appear to mediate sensitivity to the nucleotide switch through contacts to residues 36-40 of Cdc42. Discrimination between the Rho-family members is likely to be governed by GBD contacts to the switch I and alpha5 regions of the GTPases. Structural and biochemical data suggest that GBD-sequence divergence outside the CRIB motif may reflect additional regulatory interactions with functional domains that are specific to individual effectors.     

Hepatocyte growth factor-mediated attraction of mesenchymal stem cells for apoptotic neuronal and cardiomyocytic cells

Human bone marrow-derived mesenchymal stem cells (MSC) home to injured tissues and have regenerative capacity. In this study, we have investigated in vitro the influence of apoptotic and necrotic cell death, thus distinct types of tissue damage, on MSC migration. Concordant with an increased overall motility, MSC migrated towards apoptotic, but not vital or necrotic neuronal and cardiac cells. Hepatocyte growth factor (HGF) was expressed by the apoptotic cells only. MSC, in contrast, revealed expression of the HGF-receptor, c-Met. Blocking HGF bioactivity resulted in significant reduction of MSC migration. Moreover, recombinant HGF attracted MSC in a dose-dependent manner. Thus, apoptosis initiates chemoattraction of MSC via the HGF/c-Met axis, thereby linking tissue damage to the recruitment of cells with regenerative potential.