RESUMEN
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Asunto(s)
Ganglios Espinales , Células Receptoras Sensoriales , Análisis de Expresión Génica de una Sola Célula , Animales , Ratones , Ganglios Espinales/citología , Células Receptoras Sensoriales/citología , Piel/inervaciónRESUMEN
The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.
Asunto(s)
Ganglios Espinales , Mecanorreceptores , Mecanorreceptores/fisiología , Colon , Neuronas , Piel/inervaciónRESUMEN
Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-ß family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-ß2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-ß and/or Smads.
Asunto(s)
Cuerpo Estriado , Dopamina , Animales , Ratones , Mesencéfalo , Motivación , Movimiento , SinapsisRESUMEN
The encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large-scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in the primary somatosensory cortex respond to touch. Thus, mechanoreceptor subtype convergence and non-linear transformations at the earliest stage of the somatosensory hierarchy shape how touch of the skin is represented in the brain.
Asunto(s)
Mecanorreceptores , Asta Dorsal de la Médula Espinal , Animales , Ratones , Tacto/fisiología , Interneuronas , Encéfalo , Médula EspinalRESUMEN
Mammals use glabrous (hairless) skin of their hands and feet to navigate and manipulate their environment. Cortical maps of the body surface across species contain disproportionately large numbers of neurons dedicated to glabrous skin sensation, in part reflecting a higher density of mechanoreceptors that innervate these skin regions. Here, we find that disproportionate representation of glabrous skin emerges over postnatal development at the first synapse between peripheral mechanoreceptors and their central targets in the brainstem. Mechanoreceptor synapses undergo developmental refinement that depends on proximity of their terminals to glabrous skin, such that those innervating glabrous skin make synaptic connections that expand their central representation. In mice incapable of sensing gentle touch, mechanoreceptors innervating glabrous skin still make more powerful synapses in the brainstem. We propose that the skin region a mechanoreceptor innervates controls the developmental refinement of its central synapses to shape the representation of touch in the brain.
Asunto(s)
Tronco Encefálico/metabolismo , Mecanorreceptores/metabolismo , Sinapsis/metabolismo , Percepción del Tacto/fisiología , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Axones/metabolismo , Canales Iónicos/metabolismo , Ratones Noqueados , Neuronas/metabolismo , Imagen Óptica , Optogenética , Piel/inervaciónRESUMEN
Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Agonistas del GABA/farmacología , Ácidos Isonicotínicos/farmacología , Fenotipo , Células Receptoras Sensoriales/efectos de los fármacos , Tacto/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Agonistas del GABA/uso terapéutico , Ácidos Isonicotínicos/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.
Asunto(s)
Médula Espinal/citología , Médula Espinal/metabolismo , Sinapsis , Animales , Axones/metabolismo , Dendritas/metabolismo , Interneuronas/citología , Interneuronas/metabolismo , Mecanorreceptores/metabolismo , Ratones , Biología Molecular/métodos , Vías Nerviosas , Percepción del TactoRESUMEN
Patients with autism spectrum disorders (ASDs) commonly experience aberrant tactile sensitivity, yet the neural alterations underlying somatosensory dysfunction and the extent to which tactile deficits contribute to ASD characteristics are unknown. We report that mice harboring mutations in Mecp2, Gabrb3, Shank3, and Fmr1 genes associated with ASDs in humans exhibit altered tactile discrimination and hypersensitivity to gentle touch. Deletion of Mecp2 or Gabrb3 in peripheral somatosensory neurons causes mechanosensory dysfunction through loss of GABAA receptor-mediated presynaptic inhibition of inputs to the CNS. Remarkably, tactile defects resulting from Mecp2 or Gabrb3 deletion in somatosensory neurons during development, but not in adulthood, cause social interaction deficits and anxiety-like behavior. Restoring Mecp2 expression exclusively in the somatosensory neurons of Mecp2-null mice rescues tactile sensitivity, anxiety-like behavior, and social interaction deficits, but not lethality, memory, or motor deficits. Thus, mechanosensory processing defects contribute to anxiety-like behavior and social interaction deficits in ASD mouse models. PAPERCLIP.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Conducta Animal , Modelos Animales de Enfermedad , Relaciones Interpersonales , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Receptores de GABA-A/genética , Células Receptoras Sensoriales , Asta Dorsal de la Médula Espinal/metabolismo , Sinapsis/metabolismo , TactoRESUMEN
Touch perception begins with activation of low-threshold mechanoreceptors (LTMRs) in the periphery. LTMR terminals exhibit tremendous morphological heterogeneity that specifies their mechanical receptivity. In a survey of mammalian skin, we found a preponderance of neurofilament-heavy-chain(+) circumferential endings associated with hair follicles, prompting us to develop a genetic strategy to interrogate these neurons. Targeted in vivo recordings revealed them to be Aß field-LTMRs, identified 50 years ago but largely elusive thereafter. Remarkably, while Aß field-LTMRs are highly sensitive to gentle stroking of the skin, they are unresponsive to hair deflection, and they encode skin indentation in the noxious range across large, spotty receptive fields. Individual Aß field-LTMRs form up to 180 circumferential endings, making them the most anatomically expansive LTMR identified to date. Thus, Aß field-LTMRs are a major mammalian LTMR subtype that forms circumferential endings in hairy skin, and their sensitivity to gentle skin stroking arises through integration across many low-sensitivity circumferential endings.
Asunto(s)
Mecanorreceptores/metabolismo , Tacto , Animales , Axones/metabolismo , Tronco Encefálico/metabolismo , Fenómenos Electrofisiológicos , Folículo Piloso/metabolismo , Filamentos Intermedios/metabolismo , Ratones , Células Receptoras Sensoriales/metabolismo , Piel/citología , Piel/metabolismo , Asta Dorsal de la Médula Espinal/metabolismoRESUMEN
Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues1-4. The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour. We observed a high density of Krause corpuscles in the clitoris compared with the penis. Using mouse genetic tools, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of both the clitoris and penis and project to a unique sensory terminal region of the spinal cord. In vivo electrophysiology and calcium imaging experiments showed that both Krause corpuscle afferent types are A-fibre rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light-touch and mechanical vibrations (40-80 Hz) applied to the clitoris or penis. Functionally, selective optogenetic activation of Krause corpuscle afferent terminals evoked penile erection in male mice and vaginal contraction in female mice, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males and reduced sexual receptivity of females. Thus, Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours.
Asunto(s)
Clítoris , Mecanorreceptores , Pene , Conducta Sexual Animal , Tacto , Vibración , Animales , Femenino , Masculino , Ratones , Clítoris/inervación , Clítoris/fisiología , Eyaculación/fisiología , Mecanorreceptores/metabolismo , Mecanorreceptores/fisiología , Optogenética , Erección Peniana/fisiología , Pene/inervación , Pene/fisiología , Conducta Sexual Animal/fisiología , Médula Espinal/fisiología , Médula Espinal/citología , Tacto/fisiología , Vagina/fisiología , Neuronas/fisiologíaRESUMEN
The perception of touch, including the direction of stimulus movement across the skin, begins with activation of low-threshold mechanosensory neurons (LTMRs) that innervate the skin. Here, we show that murine Aδ-LTMRs are preferentially tuned to deflection of body hairs in the caudal-to-rostral direction. This tuning property is explained by the finding that Aδ-LTMR lanceolate endings around hair follicles are polarized; they are concentrated on the caudal (downward) side of each hair follicle. The neurotrophic factor BDNF is synthesized in epithelial cells on the caudal, but not rostral, side of hair follicles, in close proximity to Aδ-LTMR lanceolate endings, which express TrkB. Moreover, ablation of BDNF in hair follicle epithelial cells disrupts polarization of Aδ-LTMR lanceolate endings and results in randomization of Aδ-LTMR responses to hair deflection. Thus, BDNF-TrkB signaling directs polarization of Aδ-LTMR lanceolate endings, which underlies direction-selective responsiveness of Aδ-LTMRs to hair deflection.
Asunto(s)
Ganglios Espinales/fisiología , Folículo Piloso/fisiología , Mecanorreceptores/fisiología , Tacto , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Embrión de Mamíferos , Células Epiteliales/fisiología , Folículo Piloso/citología , Técnicas In Vitro , Mecanorreceptores/clasificación , Ratones , Receptor trkB/metabolismoRESUMEN
The somatosensory system decodes a range of tactile stimuli to generate a coherent sense of touch. Discriminative touch of the body depends on signals conveyed from peripheral mechanoreceptors to the brain through the spinal cord dorsal column and its brainstem target, the dorsal column nuclei (DCN)1,2. Models of somatosensation emphasize that fast-conducting low-threshold mechanoreceptors (LTMRs) innervating the skin drive the DCN3,4. However, postsynaptic dorsal column (PSDC) neurons within the spinal cord dorsal horn also collect mechanoreceptor signals and form a second major input to the DCN5-7. The significance of PSDC neurons and their contributions to the coding of touch have remained unclear since their discovery. Here we show that direct LTMR input to the DCN conveys vibrotactile stimuli with high temporal precision. Conversely, PSDC neurons primarily encode touch onset and the intensity of sustained contact into the high-force range. LTMR and PSDC signals topographically realign in the DCN to preserve precise spatial detail. Different DCN neuron subtypes have specialized responses that are generated by distinct combinations of LTMR and PSDC inputs. Thus, LTMR and PSDC subdivisions of the dorsal column encode different tactile features and differentially converge in the DCN to generate specific ascending sensory processing streams.
RESUMEN
Current models to explain how signals emanating from cutaneous mechanoreceptors generate representations of touch are based on comparisons of the tactile responses of mechanoreceptor subtypes and neurons in somatosensory cortex1-8. Here we used mouse genetic manipulations to investigate the contributions of peripheral mechanoreceptor subtypes to cortical responses to touch. Cortical neurons exhibited remarkably homogeneous and transient responses to skin indentation that resembled rapidly adapting (RA) low-threshold mechanoreceptor (LTMR) responses. Concurrent disruption of signals from both Aß RA-LTMRs and Aß slowly adapting (SA)-LTMRs eliminated cortical responses to light indentation forces. However, disruption of either LTMR subtype alone caused opposite shifts in cortical sensitivity but otherwise largely unaltered tactile responses, indicating that both subtypes contribute to normal cortical responses. Selective optogenetic activation of single action potentials in Aß RA-LTMRs or Aß SA-LTMRs drove low-latency responses in most mechanically sensitive cortical neurons. Similarly, most somatosensory thalamic neurons were also driven by activation of Aß RA-LTMRs or Aß SA-LTMRs. These findings support a model in which signals from physiologically distinct mechanoreceptor subtypes are extensively integrated and transformed within the subcortical somatosensory system to generate cortical representations of touch.
Asunto(s)
Percepción del Tacto , Tacto , Animales , Mecanorreceptores/fisiología , Ratones , Neuronas , Piel , Tacto/fisiologíaRESUMEN
Our sense of touch emerges from an array of mechanosensory structures residing within the fabric of our skin. These tactile end organ structures convert innocuous forces acting on the skin into electrical signals that propagate to the CNS via the axons of low-threshold mechanoreceptors (LTMRs). Our rich capacity for tactile discrimination arises from the dissimilar intrinsic properties of the LTMR subtypes that innervate different regions of the skin and the structurally distinct end organ complexes with which they associate. These end organ structures comprise a range of non-neuronal cell types, which may themselves actively contribute to the transformation of tactile forces into neural impulses within the LTMR afferents. Although the mechanism and the site of transduction across end organs remain unclear, PIEZO2 has emerged as the principal mechanosensitive channel involved in light touch of the skin. Here we review the physiological properties of LTMR subtypes and discuss how features of their cutaneous end organ complexes shape subtype-specific tuning.
Asunto(s)
Mecanorreceptores/fisiología , Piel/inervación , Tacto/fisiología , Animales , HumanosRESUMEN
The neurotrophins NGF and NT3 collaborate to support development of sympathetic neurons. Although both promote axonal extension via the TrkA receptor, only NGF activates retrograde transport of TrkA endosomes to support neuronal survival. Here, we report that actin depolymerization is essential for initiation of NGF/TrkA endosome trafficking and that a Rac1-cofilin signaling module associated with TrkA early endosomes supports their maturation to retrograde transport-competent endosomes. These actin-regulatory endosomal components are absent from NT3/TrkA endosomes, explaining the failure of NT3 to support retrograde TrkA transport and survival. The inability of NT3 to activate Rac1-GTP-cofilin signaling is likely due to the labile nature of NT3/TrkA complexes within the acidic environment of TrkA early endosomes. Thus, TrkA endosomes associate with actin-modulatory proteins to promote F-actin disassembly, enabling their maturation into transport-competent signaling endosomes. Differential control of this process explains how NGF but not NT3 supports retrograde survival of sympathetic neurons.
Asunto(s)
Actinas/metabolismo , Endosomas/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Receptor trkA/metabolismo , Factores Despolimerizantes de la Actina/metabolismo , Animales , Supervivencia Celular , Células Cultivadas , Ratones , Neurotrofina 3/metabolismo , Células PC12 , Transporte de Proteínas , Ratas , Transducción de Señal , Sistema Nervioso Simpático/citologíaRESUMEN
Innocuous touch of the skin is detected by distinct populations of neurons, the low-threshold mechanoreceptors (LTMRs), which are classified as Aß-, Aδ-, and C-LTMRs. Here, we report genetic labeling of LTMR subtypes and visualization of their relative patterns of axonal endings in hairy skin and the spinal cord. We found that each of the three major hair follicle types of trunk hairy skin (guard, awl/auchene, and zigzag hairs) is innervated by a unique and invariant combination of LTMRs; thus, each hair follicle type is a functionally distinct mechanosensory end organ. Moreover, the central projections of Aß-, Aδ-, and C-LTMRs that innervate the same or adjacent hair follicles form narrow LTMR columns in the dorsal horn. These findings support a model of mechanosensation in which the activities of Aß-, Aδ-, and C-LTMRs are integrated within dorsal horn LTMR columns and processed into outputs that underlie the perception of myriad touch sensations.
Asunto(s)
Cabello/fisiología , Mecanorreceptores/fisiología , Fenómenos Fisiológicos de la Piel , Piel/inervación , Animales , Axones/fisiología , Ratones , Neuronas/fisiología , Umbral Sensorial , Piel/citología , Médula Espinal/fisiologíaRESUMEN
More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments1-4. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.
Asunto(s)
Neurogénesis , Neuronas/fisiología , Animales , Femenino , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones , Factor de Crecimiento Nervioso/metabolismo , Neuronas/citología , ARN/análisis , ARN/genética , Análisis de la Célula Individual , Factor de Transcripción Brn-3B/genética , Factor de Transcripción Brn-3B/metabolismo , Factor de Transcripción Brn-3C/genética , Factor de Transcripción Brn-3C/metabolismoRESUMEN
The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain1-4. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.
Asunto(s)
Vías Nerviosas , Dolor/fisiopatología , Médula Espinal/citología , Médula Espinal/fisiología , Tacto/fisiología , Animales , Axones/metabolismo , Femenino , Masculino , Mecanotransducción Celular , Ratones , Filosofía , Receptores Acoplados a Proteínas G/genética , Células Receptoras Sensoriales/metabolismo , Piel/inervación , Sinapsis/metabolismoRESUMEN
The sympathetic nervous system drives brown and beige adipocyte thermogenesis through the release of noradrenaline from local axons. However, the molecular basis of higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained unknown. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific protein of the endoplasmic reticulum that we term calsyntenin 3ß. Genetic loss or gain of expression of calsyntenin 3ß in adipocytes reduces or enhances functional sympathetic innervation, respectively, in adipose tissue. Ablation of calsyntenin 3ß predisposes mice on a high-fat diet to obesity. Mechanistically, calsyntenin 3ß promotes endoplasmic-reticulum localization and secretion of S100b-a protein that lacks a signal peptide-from brown adipocytes. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. A deficiency of S100b phenocopies deficiency of calsyntenin 3ß, and forced expression of S100b in brown adipocytes rescues the defective sympathetic innervation that is caused by ablation of calsyntenin 3ß. Our data reveal a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons.