Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model.

Friedreich's ataxia (FRDA) is one of the most common hereditary ataxias. It is caused by a GAA repeat in the first intron of the FXN gene, which encodes an essential mitochondrial protein. Patients suffer from progressive motor dysfunction due to the degeneration of mechanoreceptive and proprioceptive neurons in dorsal root ganglia (DRG) and cerebellar dentate nucleus neurons, especially at early disease stages.

The making of a proprioceptor: a tale of two identities.

Proprioception, the sense of body position in space, has a critical role in the control of posture and movement. Aside from skin and joint receptors, the main sources of proprioceptive information in tetrapods are mechanoreceptive end organs in skeletal muscle: muscle spindles (MSs) and Golgi tendon organs (GTOs). The sensory neurons that innervate these receptors are divided into subtypes that detect discrete aspects of sensory information from muscles with different biomechanical functions.

Engineering mechanoreceptor feature selectivity.

Touch and proprioception rely on the discriminative abilities of distinct classes of mechanosensory neurons. In this issue of Neuron, two studies provide evidence that biomechanical mechanisms and ultrastructural cellular specializations are key contributors in defining mechanoreceptor stimulus threshold and selectivity.

The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2.

A metabotropic glutamate receptor coupled to phospholipase D (PLD-mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch-evoked firing.

Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding.

MS and GTO proprioceptor subtypes in the molecular genetic era: Opportunities for new advances and perspectives.

Proprioceptive feedback from skeletal muscle is an integral element of motor control, yet the precise physiological roles of muscle spindle (MS) and Golgi tendon organ (GTO) sensory receptors have remained difficult to disentangle due to technical limitations. New insights into the molecular basis of MS and GTO afferent subtypes offers genetic opportunities to further our understanding of the distinct functional features of these proprioceptor classes, while at the same time revealing additional layers of complexity in the regulation of coordinated motor output.

Influencers in the Somatosensory System: Extrinsic Control of Sensory Neuron Phenotypes.

Somatosensory neurons in dorsal root ganglia (DRG) comprise several main subclasses: high threshold nociceptors/thermoceptors, high- and low-threshold mechanoreceptors, and proprioceptors. Recent years have seen an explosion in the identification of molecules that underlie the functional diversity of these sensory modalities. They also have begun to reveal the developmental mechanisms that channel the emergence of this subtype diversity, solidifying the importance of peripheral instructive signals.

An expansion of the non-coding genome and its regulatory potential underlies vertebrate neuronal diversity.

Proper assembly and function of the nervous system requires the generation of a uniquely diverse population of neurons expressing a cell-type-specific combination of effector genes that collectively define neuronal morphology, connectivity, and function. How countless partially overlapping but cell-type-specific patterns of gene expression are controlled at the genomic level remains poorly understood. Here we show that neuronal genes are associated with highly complex gene regulatory systems composed of independent cell-type- and cell-stage-specific regulatory elements that reside in expanded non-coding genomic domains.

Molecular correlates of muscle spindle and Golgi tendon organ afferents.

Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents.

Regulating muscle spindle and Golgi tendon organ proprioceptor phenotypes.

Proprioception is an essential part of motor control. The main sensory subclasses that underlie this feedback control system - muscle spindle and Golgi tendon organ afferents - have been extensively characterized at a morphological and physiological level. More recent studies are beginning to reveal the molecular foundation for distinct proprioceptor subtypes, offering new insights into their developmental ontogeny and phenotypic diversity.

Airway Protection-A Role for Vagal P2RY1 Receptors.

Recent events bring the importance of respiratory health to the forefront of our collective attention. In this issue of Cell, a new study by Prescott and Umans et al. reveals how a dedicated laryngeal sensory motor reflex circuit protects our airways from aspirated foods or liquids.

A Role for Sensory end Organ-Derived Signals in Regulating Muscle Spindle Proprioceptor Phenotype.

Proprioceptive feedback from Group Ia/II muscle spindle afferents and Group Ib Golgi tendon afferents is critical for the normal execution of most motor tasks, yet how these distinct proprioceptor subtypes emerge during development remains poorly understood. Using molecular genetic approaches in mice of either sex, we identified 24 transcripts that have not previously been associated with a proprioceptor identity. Combinatorial expression analyses of these markers reveal at least three molecularly distinct proprioceptor subtypes.

Piezo2 is the principal mechanotransduction channel for proprioception.

Proprioception, the perception of body and limb position, is mediated by proprioceptors, specialized mechanosensory neurons that convey information about the stretch and tension experienced by muscles, tendons, skin and joints. In mammals, the molecular identity of the stretch-sensitive channel that mediates proprioception is unknown. We found that the mechanically activated nonselective cation channel Piezo2 was expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice.

The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian proprioceptors.

Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space.

Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings.

Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets.

The organization of spinal reflex circuits relies on the specification of distinct classes of proprioceptive sensory neurons (pSN), but the factors that drive such diversity remain unclear. We report here that pSNs supplying distinct skeletal muscles differ in their dependence on the ETS transcription factor Etv1 for their survival and differentiation. The status of Etv1-dependence is linked to the location of proprioceptor muscle targets: pSNs innervating hypaxial and axial muscles depend critically on Etv1 for survival, whereas those innervating certain limb muscles are resistant to Etv1 inactivation.

Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord.

Different functional classes of dorsal root ganglion sensory neurons project their axons to distinct target zones within the developing spinal cord. To explore the mechanisms that link sensory neuron subtype identity and axonal projection pattern, we analyzed the roles of Runx and ETS transcription factors in the laminar targeting of sensory afferents. Gain- and loss-of-function studies in chick embryos reveal that the status of Runx3 expression is a major determinant of the dorso-ventral position of termination of proprioceptive and cutaneous sensory axons.

A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.

Subpopulations of sensory neurons in the dorsal root ganglion (DRG) can be characterized on the basis of sensory modalities that convey distinct peripheral stimuli, but the molecular mechanisms that underlie sensory neuronal diversification remain unclear. Here, we have used genetic manipulations in the mouse embryo to examine how Runx transcription factor signaling controls the acquisition of distinct DRG neuronal subtype identities. Runx3 acts to diversify an Ngn1-independent neuronal cohort by promoting the differentiation of proprioceptive sensory neurons through erosion of TrkB expression in prospective TrkC+ sensory neurons.

Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.

In mammals, the perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by nociceptive sensory neurons. The molecular mechanisms responsible for the specification of distinct sensory modality are, however, largely unknown. We show here that Runx1, a Runt domain transcription factor, is expressed in most nociceptors during embryonic development but in adult mice, becomes restricted to nociceptors marked by expression of the neurotrophin receptor Ret.