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Despite the potential importance of genital mechanosensation for sexual reproduction, little is known about how perineal touch influences mating. We explored how mechanosensation affords exquisite awareness of the genitals and controls reproduction in mice and humans. Using genetic strategies and in vivo functional imaging, we demonstrated that the mechanosensitive ion channel PIEZO2 (piezo-type mechanosensitive ion channel component 2) is necessary for behavioral sensitivity to perineal touch. PIEZO2 function is needed for triggering a touch-evoked erection reflex and successful mating in both male and female mice. Humans with complete loss of PIEZO2 function have genital hyposensitivity and experience no direct pleasure from gentle touch or vibration. Together, our results help explain how perineal mechanoreceptors detect the gentlest of stimuli and trigger physiologically important sexual responses, thus providing a platform for exploring the sensory basis of sexual pleasure and its relationship to affective touch.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

Henry Miller stated that "to relieve a full bladder is one of the great human joys". Urination is critically important in health and ailments of the lower urinary tract cause high pathological burden. Although there have been advances in understanding the central circuitry in the brain that facilitates urination 1-3 , there is a lack of in-depth mechanistic insight into the process. In addition to central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow 4 . The mechanotransduction molecules and cell types that function as the primary stretch and pressure detectors in the urinary tract mostly remain unknown. Here we identify expression of the mechanosensitive ion channel PIEZO2 in lower urinary tract tissues, where it is required for low-threshold bladder-stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Humans and mice lacking functional PIEZO2 have impaired bladder control, and humans lacking functional PIEZO2 report deficient bladder-filling sensation. This study identifies PIEZO2 as a key mechanosensor in urinary function. These findings set the foundation for future work to identify the interactions between urothelial cells and sensory neurons that control urination.

Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

PIEZO2 is a large stretch-gated ion channel highly expressed in specific sensory neurons which mediates human mechanosensation. Individuals with biallelic loss of function (LOF) variants in the PIEZO2 gene highlight the impact of the congenital absence of specific mechanotransduction-dependent senses, including proprioception aspects of touch and interception. We report on twelve unrelated individuals (except one sibling pair), ranging in age from 4 years to 42 years old with biallelic PIEZO2 LOF, and report on detailed neurological examination, neurophysiology, and evaluations of pulmonary, gastrointestinal and urinary function. We identified common early neonatal and developmental consequences of PIEZO2 LOF including: reduced fetal movements (n=6), hypotonia (n=12), neonatal respiratory distress (n=9), and feeding difficulty (n=11). The age at achievement of independent ambulation (n=8) was markedly delayed (5-16 years old). Pseudoathetosis was frequently clinically observed. Orthopedic and systemic findings included: congenital hip dysplasia (n=11), arthrogryposis (n=12), early progressive scoliosis (n=12), constipation (n=11), reduced voiding frequency (n=10). The findings in these participants with LOF in PIEZO2 recapitulates what is observed in preclinical models, and highlights the developmental, motor functional, systemic, and orthopedic consequences of absent mechanotransduction and proprioception. Initially slow but improving functional gains over time suggest that these maturational processes may rely on emerging executive and motor planning skills combined with visual compensatory input. This expanded series represents the largest cohort of individuals with PIEZO2 LOF across a wide age range. Recognizing and elucidating this PIEZO2-related phenotype improves our understanding of human sensory perception and allows for development of rehabilitative measures aimed at compensatory recruitment of intact sensory modalities to optimize function. [ABSTRACT FROM AUTHOR]