Subject(s)
Neoplasms , Clinical Trials as Topic , Humans , Neoplasms/therapy , Patient-Centered CareABSTRACT
Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the "atopic march." Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.
Subject(s)
Cytokines/metabolism , Dermatitis, Atopic/pathology , Signal Transduction , Animals , Calcium/metabolism , Cells, Cultured , Dermatitis, Atopic/metabolism , Humans , Immunoglobulins/metabolism , Keratinocytes/metabolism , Pruritus/immunology , Receptors, Cytokine/metabolism , Sensory Receptor Cells/metabolism , Skin/metabolism , Skin/pathology , TRPA1 Cation Channel , Transient Receptor Potential Channels/metabolism , Thymic Stromal LymphopoietinABSTRACT
Although the neurobiology of rodent facial whiskers has been studied intensively, little is known about sensing in other vibrissae. Here we describe the under-investigated submandibular "whisker trident" on the rat's chin. In this three-whisker array, a unique unpaired midline whisker is laterally flanked by two slightly shorter whiskers. All three whiskers point to the ground and are curved backwards. Unlike other whiskers, the trident is not located on an exposed body part. Trident vibrissae are not whisked and do not touch anything over long stretches of time. However, trident whiskers engage in sustained ground contact during head-down running while the animal is exploring or foraging. In biomechanical experiments, trident whiskers follow caudal ground movement more smoothly than facial whiskers. Remarkably, deflection angles decrease with increasing ground velocity. We identified one putative trident barrel in the left somatosensory cortex and two barrels in the right somatosensory cortex. The elongated putative trident-midline barrel is the longest and largest whisker barrel, suggesting that the midline trident whisker is of great functional significance. Cortical postsynaptic air-puff responses in the trident representation show much less temporal precision than facial whisker responses. Trident whiskers do not provide as much high-resolution information about object contacts as facial whiskers. Instead, our observations suggest an idiothetic function: their biomechanics allow trident whiskers to derive continuous measurements about ego motion from ground contacts. The midline position offers unique advantages in sensing heading direction in a laterally symmetric manner. The changes in trident deflection angle with velocity suggest that trident whiskers might function as a tactile speedometer.
Subject(s)
Afferent Pathways/physiology , Movement/physiology , Somatosensory Cortex/physiology , Touch , Vibrissae/anatomy & histology , Vibrissae/innervation , Action Potentials/physiology , Animals , Biomechanical Phenomena , Brain Mapping , Excitatory Postsynaptic Potentials/physiology , Female , Functional Laterality , Inhibitory Postsynaptic Potentials/physiology , Male , Mice , Mice, Inbred C57BL , Neurons/physiology , Patch-Clamp Techniques , Physical Stimulation , Rats , Rats, Long-Evans , Somatosensory Cortex/cytology , Touch Perception/physiology , Video RecordingABSTRACT
Core components of cytokinesis are conserved from yeast to human, but how these components are assembled into a robust machine that drives cytokinesis remains poorly understood. In this paper, we show by fluorescence recovery after photobleaching analysis that Myo1, the sole myosin-II in budding yeast, was mobile at the division site before anaphase and became immobilized shortly before cytokinesis. This immobility was independent of actin filaments or the motor domain of Myo1 but required a small region in the Myo1 tail that is thought to be involved in higher-order assembly. As expected, proteins involved in actin ring assembly (tropomyosin and formin) and membrane trafficking (myosin-V and exocyst) were dynamic during cytokinesis. Strikingly, proteins involved in septum formation (the chitin synthase Chs2) and/or its coordination with the actomyosin ring (essential light chain, IQGAP, F-BAR, etc.) displayed Myo1-dependent immobility during cytokinesis, suggesting that Myo1 plays a scaffolding role in the assembly of a cytokinesis machine.
