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The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4+SNS-Cre/TdTomato+, 2) IB4−SNS-Cre/TdTomato+, and 3) Parv-Cre/TdTomato+ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. In the nervous system, a network of specialized neurons—known as the somatosensory system—carries information about sensations including touch, muscle position, temperature and pain. Distinct sets of somatosensory neurons are thought to carry information about the different types of sensations. In young animals, the precise switching on, or ‘expression’, of genes controls the formation of the network of neurons. However, it is not known exactly which genes are expressed in what types of neurons, where, or when. Here, Chiu et al. used a technique called flow cytometry using different fluorescent markers to isolate a group of cells called Dorsal Root Ganglion (DRG) neurons in mice. These neurons have long thread-like fibers that extend from the spinal cord to the skin, muscles and joints all over the body. These fibers carry sensory information to the spinal cord, where it can be relayed to the brain and processed. The experiments compared three distinct types of DRG neuron and found that they differed in their ability to send information to other cells. Chiu et al. analyzed the expression of all the genes in the three types of DRG neurons. Each type of neuron had distinct groups of genes that were being expressed. Also, several genes that are known to be important for sensation were expressed at different levels in the different types of cells. Next, large numbers of single cells were analyzed to find out the finer details about the three types of neuron. These findings made it possible to further divide the DRG neurons into six distinct subsets that matched previously known groups of somatosensory neurons, and also identified new ones. Chiu et al.'s findings reveal the complexity and diversity of the neurons involved in carrying information about sensations towards the brain. This is an important step in classifying the nervous system, and uncovers many genes previously not linked to sensation. The next challenges lie in understanding how the expression of these genes in each type of neuron relates to their unique roles.

The AgRP-expressing neurons in the arcuate nucleus drive food-seeking behaviours during caloric restriction; a mouse study of monosynaptic retrograde rabies spread and optogenetic circuit mapping reveals that these neurons are activated by input from hypothalamic paraventricular nucleus cells and their activation or inhibition can modulate feeding behaviour. The neurons that prescribe hunger Increasing activity of the AgRP neurons in the hypothalamus drives food-seeking behaviours during periods of calorie restriction. The source of the input that provokes this hunger response was unknown. Bradford Lowell and colleagues have now mapped the inputs into these AgRP neurons and demonstrate that the paraventricular nucleus, normally thought of as a satiety centre, contains orexigenic neurons that drive AgRP neurons and food-seeking in mice, even when the mouse was otherwise sated. This work establishes specific populations of paraventricular nucleus neurons as drivers of a powerful hub within the feeding circuit. Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake 1 , 2 , 3 , 4 , 5 . Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding 3 , 6 , 7 . Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity 8 , 9 , 10 . Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

Inhibition of T cell–derived leukocyte elastase by neuronal SerpinA3N or the drug Sivelestat reduces neuropathic pain. Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy 1 , 2 , 3 , 4 , classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation 5 . To circumvent this, we used two outbred lines of rats 6 , which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity 7 . SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis. [PUBLICATION ABSTRACT]

Metastasis is a fatal complication of prostate cancer, but its mechanisms remain largely unknown. In this report, the authors identify a signaling pathway commonly deregulated in human prostate cancer and describe how it can foster both primary growth and metastatic tumor progression. Epigenetic silencing of the RasGAP DAB2IP by EZH2 overexpression results in aberrant activation of Ras signaling, but also of NF-κB. These two events are mediated by different DAB2IP domains and have distinct roles in localized growth and distant dissemination. Metastasis is responsible for the majority of prostate cancer–related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene–tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-κB (NF-κB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-κB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N -methyltransferase EZH2 activates Ras and NF-κB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

Chiu IM, Barrett LB, Williams EK, Strochlic DE, Lee S, Weyer AD, Lou S, Bryman G, Roberson DP, Ghasemlou N, Piccoli C, Ahat E, Wang V, Cobos EH, Stucky CL, Ma Q, Liberles SD, Woolf C. 2014. Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity. eLife 3:04660. doi: 10.7554/eLife.04660 Published 19 December 2014 Supplementary file 1 was missing values and the FDR values shown in Column K were incorrect as a result.

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to its control. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1-5. Consistent with their obligatory role in regulating appetite, genetic ablation or pharmacogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is key in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric state-dependent synaptic plasticity8-10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing Thyrotropin-releasing hormone (TRH) and Pituitary adenylate cyclase-activating polypeptide (PACAP). Pharmaco-genetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

The vagus nerve serves as a primary neural link between the brain and internal organs, detecting a variety of physiological stimuli and controlling a range of autonomic functions essential to homeostatic regulation. However, despite its fundamental importance, little is known about the repertoire of sensory mechanisms residing in vagal afferents, the cellular logic of information coding within the vagus nerve, and the central representation of internal physiological states. To dissect the neural circuits underlying viscerosensation, we adopted a genome-guided strategy to classify vagal sensory neurons based on G-protein-coupled receptor (GPCR) expression. We identified 5 principal cell types and obtained genetic access to these neurons in vivo using GPCR- ires-cre mouse strains. Using a combination of approaches that support cell-type specific analysis, we investigated the anatomical projections, response profiles, and physiological function of discrete vagal sensory subtypes. Within the respiratory system, we identified two vagal sensory populations that exert powerful and opposing effects on breathing. P2ry1- and Npy2r-expressing neurons innervate distinct anatomical structures in the lung and send projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers while P2ry1 neurons are fast conducting A fibers. Optogenetic activation of Npy2r neurons induces rapid and shallow breathing whereas activating P2ry1 neurons acutely silences respiration, trapping animals in exhalation. Furthermore, activating P2ry1 neurons had no effect on heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.