ABSTRACT
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. We show here that Whirlin/Deafness autosomal recessive 31 (DFNB31), a PDZ-scaffold protein involved in vestibular and auditory hair cell transduction, is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice. Whirlin localizes to the peripheral sensory endings of pSNs and facilitates pSN afferent firing in response to muscle stretch. The requirement of Whirlin in both proprioceptors and hair cells suggests that accessory mechanosensory signaling molecules define common features of mechanoreceptive processing across sensory systems.
Subject(s)
Membrane Proteins/metabolism , Muscle Spindles/physiology , Sensory Receptor Cells/metabolism , Signal Transduction/physiology , Animals , Cells, Cultured , Early Growth Response Protein 2/genetics , Early Growth Response Protein 2/metabolism , Ganglia, Spinal/cytology , Gene Expression Profiling , Hair Cells, Auditory/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Luminescent Proteins/genetics , Membrane Proteins/genetics , Mice , Mice, Transgenic , Muscle, Skeletal/cytology , Neural Conduction/drug effects , Neural Conduction/genetics , Oligonucleotide Array Sequence Analysis , Parvalbumins/genetics , Parvalbumins/metabolism , Sensory Receptor Cells/drug effects , Signal Transduction/drug effects , Wheat Germ Agglutinins/genetics , Wheat Germ Agglutinins/metabolism , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
Locomotion is controlled by spinal networks that generate rhythm and coordinate left-right and flexor-extensor patterning. Defined populations of spinal interneurons have been linked to patterning circuits; however, neurons comprising the rhythm-generating kernel have remained elusive. Here, we identify an ipsilaterally projecting excitatory interneuron population, marked by the expression of Shox2 that overlaps partially with V2a interneurons. Optogenetic silencing or blocking synaptic output of Shox2 interneurons (INs) in transgenic mice perturbed rhythm without an effect on pattern generation, whereas ablation of the Shox2 IN subset coinciding with the V2a population was without effect. Most Shox2 INs are rhythmically active during locomotion and analysis of synaptic connectivity showed that Shox2 INs contact other Shox2 INs, commissural neurons, and motor neurons, with preference for flexor motor neurons. Our findings focus attention on a subset of Shox2 INs that appear to participate in the rhythm-generating kernel for spinal locomotion.
Subject(s)
Homeodomain Proteins/physiology , Interneurons/physiology , Locomotion/physiology , Animals , Axons/physiology , Dependovirus/genetics , Electrophysiological Phenomena , Excitatory Amino Acid Agonists/pharmacology , Gene Silencing , Glutamic Acid/physiology , Immunohistochemistry , In Situ Hybridization , Locomotion/drug effects , Male , Mice , Motor Neurons/physiology , N-Methylaspartate/pharmacology , Neural Pathways/physiology , Optogenetics , Serotonin/pharmacology , Spinal Cord/cytology , Spinal Cord/physiology , Vesicular Glutamate Transport Protein 2/physiologyABSTRACT
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. The level of NT3 expression in individual muscles correlates with Etv1-dependence and the loss of pSNs triggered by Etv1 inactivation can be prevented by elevating the level of muscle-derived NT3-revealing a TrkC-activated Etv1-bypass pathway. Our findings support a model in which the specification of aspects of pSN subtype character is controlled by variation in the level of muscle NT3 expression and signaling.
