1. Joint Public Review:

    Although sensory neurons are thought to be the primary detectors of environmental stimuli in skin, it is more and more appreciated that non-neuronal cell types also play important roles. Previous work from the Stucky group (and others) has shown stimulation of optical excitation of keratinocytes can evoke action potentials in sensory neurons and behavioral responses suggesting functional connectivity. Earlier work from the Stucky group provided evidence that keratinocytes are thermosenstive and required for normal temperature sensation.

    Here, they look into whether these cells are also important for mechanosensation. Using K14-Cre-dependent conditional KO mice, functional assays and behavioral analysis, Moehring and collaborators report that the mechanosensitive channel Piezo1 is expressed in keratinocytes in mice and humans and claim that it contributes to normal touch sensation. The in vitro data convincingly show that keratinocytes have mechanically evoked currents mediated by Piezo1. Interestingly, this work shows that recruitment of epidermal, non-neuronal Piezo1 by mechanical stimulation of keratinocytes could contribute significantly to touch through activation of cutaneous sensory fibers (mechanoreceptors). Specifically, they provide evidence that removing Piezo1 from keratinocytes reduces the frequency of spiking in select types of sensory neurons to punctate and dynamic touch stimuli. Finally, they supply quite surprising data documenting significant behavioral deficits in Krt-conditional knockout mice.

    Overall, this work provides an intriguing series of observation and potentially fundamental discovery. However, concerns remain as to how the relatively subtle differences in the skin-nerve recordings result in such profound behavioral effects? Similarly, it is hard to understand how loss of the related channel Piezo2 in sensory neurons completely abolishes many touch responses if mechanosensitivity of keratinocytes is sufficient to evoke touch behaviors (as their experiments applying Yoda-1 to the hindpaw of mice would suggest). Altogether, this work suggests a novel role for epidermal Piezo1 in normal touch but the key neuro-epithelial signaling remains to be identified.

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  2. Evaluation Summary:

    This manuscript is of broad interest to readers in the field of somatosensation. The identification that a common type of skin cell responds to mechanical force using a specific molecular receptor called Piezo1 is an important contribution to our understanding of mechanotransduction. A combination of conditional gene knockout with physiological and behavioral assays provides intriguing evidence that communication between skin and nerves is important for normal touch sensation, a conclusion that if further supported by additional data could become a fundamental discovery.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

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