Cell metabolism, 18(6), 860–870.
Xu, Y, Wu Z, Sun H, Zhu Y, Kim ER, Lowell BB, Arenkiel BR, Xu Y, Tong Q (2013).
PMID: 24315371 | DOI: 10.1016/j.cmet.2013.11.003.
The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.
Proc Natl Acad Sci U S A. 2018 Dec 12.
Mathieu M, Drelon C, Rodriguez S, Tabbal H, Septier A, Damon-Soubeyrand C, Dumontet T, Berthon A, Sahut-Barnola I, Djari C, Batisse-Lignier M, Pointud JC, Richard D, Kerdivel G, Calméjane MA, Boeva V, Tauveron I, Lefrançois-Martinez AM, Martinez A, Val P.
PMID: 30541888 | DOI: 10.1073/pnas.1809185115
Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
Frezel, N;Ranucci, M;Foster, E;Wende, H;Pelczar, P;Mendes, R;Ganley, RP;Werynska, K;d'Aquin, S;Beccarini, C;Birchmeier, C;Zeilhofer, HU;Wildner, H;
PMID: 36947543 | DOI: 10.1016/j.celrep.2023.112295
Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-MafEX) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-MafEX neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-MafEX neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-MafEX neuron activation. Our study identifies c-MafEX neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.
Qi, H;Luo, L;Lu, C;Chen, R;Zhou, X;Zhang, X;Jia, Y;
PMID: 36782064 | DOI: 10.1038/s41380-023-01993-5
Vocalization is an essential medium for social signaling in birds and mammals. Periaqueductal gray (PAG) a conserved midbrain structure is believed to be responsible for innate vocalizations, but its molecular regulation remains largely unknown. Here, through a mouse forward genetic screening we identified one of the key Wnt/β-catenin effectors TCF7L2/TCF4 controls ultrasonic vocalization (USV) production and syllable complexity during maternal deprivation and sexual encounter. Early developmental expression of TCF7L2 in PAG excitatory neurons is necessary for the complex trait, while TCF7L2 loss reduces neuronal gene expressions and synaptic transmission in PAG. TCF7L2-mediated vocal control is independent of its β-catenin-binding domain but dependent of its DNA binding ability. Patient mutations associated with developmental disorders, including autism spectrum disorders, disrupt the transcriptional repression effect of TCF7L2, while mice carrying those mutations display severe USV impairments. Therefore, we conclude that TCF7L2 orchestrates gene expression in midbrain to control vocal production through its DNA binding but not transcription activation domain.
Warwick, C;Salsovic, J;Hachisuka, J;Smith, KM;Sheahan, TD;Chen, H;Ibinson, J;Koerber, HR;Ross, SE;
PMID: 36057681 | DOI: 10.1038/s41467-022-32608-2
Allodynia is a state in which pain is elicited by innocuous stimuli. Capsaicin applied to the skin results in an allodynia that extends to a broad region beyond the application site. This sensitization is thought to be mediated by spinal networks; however, we do not have a clear picture of which spinal neurons mediate this phenomenon. To address this gap, we used two-photon calcium imaging of excitatory interneurons and spinal projection neurons in the mouse spinal dorsal horn. To distinguish among neuronal subtypes, we developed CICADA, a cell profiling approach to identify cell types during calcium imaging. We then identified capsaicin-responsive and capsaicin-sensitized neuronal populations. Capsaicin-sensitized neurons showed emergent responses to innocuous input and increased receptive field sizes consistent with psychophysical reports. Finally, we identified spinal output neurons that showed enhanced responses from innocuous input. These experiments provide a population-level view of central sensitization and a framework with which to model somatosensory integration in the dorsal horn.
Scales, MK;Velez-Delgado, A;Steele, NG;Schrader, HE;Stabnick, AM;Yan, W;Mercado Soto, NM;Nwosu, ZC;Johnson, C;Zhang, Y;Salas-Escabillas, DJ;Menjivar, RE;Maurer, HC;Crawford, HC;Bednar, F;Olive, KP;Pasca di Magliano, M;Allen, BL;
PMID: 35867772 | DOI: 10.1371/journal.pgen.1010315
Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.
Zhang, Y;Roy, DS;Zhu, Y;Chen, Y;Aida, T;Hou, Y;Shen, C;Lea, NE;Schroeder, ME;Skaggs, KM;Sullivan, HA;Fischer, KB;Callaway, EM;Wickersham, IR;Dai, J;Li, XM;Lu, Z;Feng, G;
PMID: 35676479 | DOI: 10.1038/s41586-022-04806-x
Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.
Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, Gould SE, de Sauvage FJ.
PMID: 30297801 | DOI: 10.1038/s41586-018-0596-y
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)1, residual disease persists in some patients and may contribute to relapse when treatment is discontinued2. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC3 and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
Rizzi G, Coban M, Tan KR.
PMID: 31113944 | DOI: 10.1038/s41467-019-10223-y
The red nucleus (RN) is required for limb control, specifically fine motor coordination. There is some evidence for a role of the RN in reaching and grasping, mainly from lesion studies, but results so far have been inconsistent. In addition, the role of RN neurons in such learned motor functions at the level of synaptic transmission has been largely neglected. Here, we show that Vglut2-expressing RN neurons undergo plastic events and encode the optimization of fine movements. RN light-ablation severely impairs reaching and grasping functions while sparing general locomotion. We identify a neuronal population co-expressing Vglut2, PV and C1QL2, which specifically undergoes training-dependent plasticity. Selective chemo-genetic inhibition of these neurons perturbs reaching and grasping skills. Our study highlights the role of the Vglut2-positive rubral population in complex fine motor tasks, with its related plasticity representing an important starting point for the investigation of mechanistic substrates of fine motor coordination training.
Peng, J;Li, F;Wang, J;Wang, C;Jiang, Y;Liu, B;He, J;Yuan, K;Pan, C;Lin, M;Zhou, B;Chen, L;Gao, D;Zhao, Y;
PMID: 36316325 | DOI: 10.1038/s41421-022-00474-3
In adults, hepatocytes are mainly replenished from the existing progenitor pools of hepatocytes and cholangiocytes during chronic liver injury. However, it is unclear whether other cell types in addition to classical hepatocytes and cholangiocytes contribute to hepatocyte regeneration after chronic liver injuries. Here, we identified a new biphenotypic cell population that contributes to hepatocyte regeneration during chronic liver injuries. We found that a cell population expressed Gli1 and EpCAM (EpCAM+Gli1+), which was further characterized with both epithelial and mesenchymal identities by single-cell RNA sequencing. Genetic lineage tracing using dual recombinases revealed that Gli1+ nonhepatocyte cell population could generate hepatocytes after chronic liver injury. EpCAM+Gli1+ cells exhibited a greater capacity for organoid formation with functional hepatocytes in vitro and liver regeneration upon transplantation in vivo. Collectively, these findings demonstrate that EpCAM+Gli1+ cells can serve as a new source of liver progenitor cells and contribute to liver repair and regeneration.
Chen, Z;Chen, G;Zhong, J;Jiang, S;Lai, S;Xu, H;Deng, X;Li, F;Lu, S;Zhou, K;Li, C;Liu, Z;Zhang, X;Zhu, Y;
PMID: 36028570 | DOI: 10.1038/s41380-022-01742-0
Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding. LSNts neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LSNts→the supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LSNts neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LSNts or LSNts→TU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LSNts→TU is a key pathway in regulating hedonic feeding.
Arid1a-Plagl1-Hh signaling is indispensable for differentiation-associated cell cycle arrest of tooth root progenitors
Du, J;Jing, J;Yuan, Y;Feng, J;Han, X;Chen, S;Li, X;Peng, W;Xu, J;Ho, TV;Jiang, X;Chai, Y;
PMID: 33826897 | DOI: 10.1016/j.celrep.2021.108964
Chromatin remodelers often show broad expression patterns in multiple cell types yet can elicit cell-specific effects in development and diseases. Arid1a binds DNA and regulates gene expression during tissue development and homeostasis. However, it is unclear how Arid1a achieves its functional specificity in regulating progenitor cells. Using the tooth root as a model, we show that loss of Arid1a impairs the differentiation-associated cell cycle arrest of tooth root progenitors through Hedgehog (Hh) signaling regulation, leading to shortened roots. Our data suggest that Plagl1, as a co-factor, endows Arid1a with its cell-type/spatial functional specificity. Furthermore, we show that loss of Arid1a leads to increased expression of Arid1b, which is also indispensable for odontoblast differentiation but is not involved in regulation of Hh signaling. This study expands our knowledge of the intricate interactions among chromatin remodelers, transcription factors, and signaling molecules during progenitor cell fate determination and lineage commitment.
