These proteins have been shown to regulate mitotic spindle orientation in various tissues and organisms and are of crucial importance to centriole positioning from flies to mammals 10, 11. Cell‐intrinsic planar polarity is controlled by the asymmetric enrichment of GTP‐binding protein alpha‐I subunit 3 (Gα i3), G‐protein‐signalling modulator 2 (GPSM2 or LGN), mammalian inscuteable (mInsc) and the atypical protein kinase C zeta (aPKC). Tissue planar polarity is governed by the so‐called core planar cell polarity (PCP) proteins, which include Van Gogh‐like (Vangl1 and Vangl2), Frizzled (Fz3 and Fz6) and Dishevelled 7, 8, 9. Both levels of polarity are dependent upon the asymmetric distribution of specific proteins in opposing medio‐lateral domains 6. This is referred to as “tissue planar polarity” and is most obviously indicated by the vertex of the stereociliary bundles pointing towards the lateral side of the epithelium. In addition to this cell‐intrinsic planar polarity, all HCs are co‐ordinately oriented in the plane of the epithelium-along the medio‐lateral axis of the OC. This organelle is a v‐shaped bundle of actin‐rich microvilli (named stereocilia) that emerges in close association with the HC's specialized primary cilium (named the kinocilium). Each HC develops a highly polarized mechanosensitive organelle at its apical surface to detect sound signals. As the differentiation of HCs proceeds, these cells acquire dual levels of planar polarity, both of which are crucial for auditory perception. The SGNs are born early during development and start extending their peripheral processes towards the sensory epithelium (the organ of Corti, OC) before their target HCs have differentiated 5. Most of the cells composing the cochlea derive from the otic placode, which consists of a thickened region of neuroectoderm. However, little is known about the importance of managing the proteome during the development of the auditory portion of the inner ear. The ability to maintain proteostasis declines with age, and numerous age‐related diseases have been linked to proteostatic disruption, including age‐related hearing loss 4. Under pathological stress, these protein quality control systems can be overwhelmed and the accumulation of misfolded proteins can lead to cell death 3. Polyubiquitinated proteins that fail to be degraded by the proteasome are transported along microtubules towards the microtubule‐organizing centre (MTOC), where they gather to form a cytoprotective structure called an aggresome. the ubiquitin–proteasome system and autophagy 2. Protein homeostasis (herein referred to as proteostasis) is reliant upon chaperones that assist protein folding or re‐folding, and on their principal degradation systems, i.e. Misfolded proteins are detrimental to cellular homeostasis because of their propensity to self‐aggregate and aberrantly interact with other cellular components, disrupting normal cellular processes. There is increasing evidence that protein misfolding and aggregation are involved in hearing loss caused by environmental factors such as exposure to noise and ototoxic drugs 1. the so‐called hair cells (HCs)-or to their innervating spiral ganglion neurons (SGNs). Sensorineural hearing loss, affecting millions of people worldwide, results from damage to the cochlear mechanosensory cells-i.e. Our study highlights the importance of developmental proteostasis in the cochlea and unveils an unexpected link between proteome integrity and polarized organization of cellular components. Alleviation of protein misfolding using the chemical chaperone 4‐phenylbutyric acid during embryonic development ameliorates hair cell polarity in Elp3‐deficient animals. We demonstrate that protein aggregates accumulate at the apical surface of hair cells, where they cause a local slowdown of microtubular trafficking, altering the distribution of intrinsic polarity proteins and affecting kinocilium position and length. The cochlear mechanosensory cells are able to survive proteostasis disruption but suffer defects in polarity and stereociliary bundle morphogenesis. In the absence of the catalytic subunit Elp3, differentiating spiral ganglion neurons display large aggresome‐like structures and undergo apoptosis before birth. Here, we show that altered proteostasis consequent to Elongator complex deficiency also impacts the proper development of the cochlea and results in deafness. Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age‐related diseases, including hearing loss.
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