Summary The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain 1 – 4 . Projection neurons (PNs) of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery channel through these spinal PNs en route to the brain. However, the organizational logic of the anterolateral pathway remains elusive. Here, we show that two PN populations that express structurally related GPCRs, TACR1 and GPR83, form parallel ascending circuit modules that cooperate to convey tactile, thermal and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons (PBN L ). Axons of Tacr1 - and Gpr83 -expressing spinoparabrachial (SPB) neurons innervate distinct sets of PBN L subnuclei, and strong optogenetic stimulation of their axon terminals induces distinct escape behaviors and autonomic responses. Moreover, Gpr83 -expressing SPB neurons are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Remarkably, the valence associated with activation of Gpr83 -expressing SPB neurons is either positive or negative depending on stimulus intensity. These findings reveal anatomically, physiologically, and functionally distinct SPB tract subdivisions that underlie affective aspects of touch and pain.

Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli. The anatomical receptive fields of these two mechanoreceptor subtypes homotypically tile glabrous skin in a manner that is offset with respect to one another. Electron microscopic analysis of the two Meissner afferents within the corpuscle supports a model in which the extent of lamellar cell wrappings of mechanoreceptor endings determines their force sensitivity thresholds and kinetic properties.

SUMMARY The ocular motility disorder “Congenital fibrosis of the extraocular muscles type 1″ (CFEOM1) results from heterozygous mutations altering the motor and 3rd coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knock-in mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve’s superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a interacting protein and report that Map1b−/− mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1, and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.