Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine

Yang, Lanbo; Xu, Mengyi; Bhuiyan, Shamsuddin A.; Li, Jia; Zhao, Jun; Cohrs, Randall J.; Susterich, Justin T.; Signorelli, Sylvia; Green, Ursula; Stone, James R.; Levy, Dan; Lennerz, Jochen K.; Renthal, William

doi:10.1016/j.neuron.2022.03.003

Cited by 82 publications

(139 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was supported by qualitative assessment indicating that colocalization did not tend to occur in NF200 (an A-fiber marker) expressing neurons ( Ruscheweyh et al, 2007 ). Additionally, single cell mRNA expression data from a TG atlas indicates that CGRP and CTR mRNA are both present in non-A-fiber, peptidergic and non-peptidergic nociceptor neurons in the mouse TG ( Yang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons

et al. 2022

View full text Add to dashboard Cite

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminal ganglia, a key site in craniofacial pain and migraine. CGRP potently activates two receptors: the CGRP receptor and the AMY1 receptor. These receptors are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with either the calcitonin receptor-like receptor (CLR) to form the CGRP receptor or the calcitonin receptor (CTR) to form the AMY1 receptor. The expression of the CGRP receptor in trigeminal ganglia has been described in several studies; however, there is comparatively limited data available describing AMY1 receptor expression and in which cellular subtypes it is found. This research aimed to determine the relative distributions of the AMY1 receptor subunit, CTR, and CGRP in neurons or glia in rat, mouse and human trigeminal ganglia. Antibodies against CTR, CGRP and neuronal/glial cell markers were applied to trigeminal ganglia sections to investigate their distribution. CTR-like and CGRP-like immunoreactivity were observed in both discrete and overlapping populations of neurons. In rats and mice, 30–40% of trigeminal ganglia neurons displayed CTR-like immunoreactivity in their cell bodies, with approximately 78–80% of these also containing CGRP-like immunoreactivity. Although human cases were more variable, a similar overall pattern of CTR-like immunoreactivity to rodents was observed in the human trigeminal ganglia. CTR and CGRP appeared to be primarily colocalized in small to medium sized neurons, suggesting that colocalization of CTR and CGRP may occur in C-fiber neurons. CGRP-like or CTR-like immunoreactivity were not typically observed in glial cells. Western blotting confirmed that CTR was expressed in the trigeminal ganglia of all three species. These results confirm that CTR is expressed in trigeminal ganglia neurons. The identification of populations of neurons that express both CGRP and CTR suggests that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY1 receptor. Overall, this suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.

show abstract

Section: Discussionmentioning

confidence: 99%

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Although many aspects of purinergic signaling have been elucidated, currently little is known about the transcriptional features of purinergic signaling in TG. In recent years, scRNA-seq and single nucleus RNA sequencing technologies have been used to investigate heterogeneity of peripheral ganglia ( Usoskin et al, 2015 ; Nguyen et al, 2017 ; Mapps et al, 2022 ; Yang et al, 2022 ) and transcriptional features of functional gene sets such as transcription factors at the single cell level ( Paul et al, 2017 ; Li et al, 2021 ). In this study, we revealed the shared and unique expression patterns of genes associated with purinergic signaling in distinct cell types, suggesting that the multidirectional action of purinergic signaling in TG is cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals distinct transcriptional features of the purinergic signaling in mouse trigeminal ganglion

Jia

Liu²,

Chu³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Trigeminal ganglion (TG) is the first station of sensory pathways in the orofacial region. The TG neurons communicate with satellite glial cells (SGCs), macrophages and other cells forming a functional unit that is responsible for processing of orofacial sensory information. Purinergic signaling, one of the most widespread autocrine and paracrine pathways, plays a crucial role in intercellular communication. The multidirectional action of purinergic signaling in different cell types contributes to the neuromodulation and orofacial sensation. To fully understand the purinergic signaling in these processes, it is essential to determine the shared and unique expression patterns of genes associated with purinergic signaling in different cell types. Here, we performed single-cell RNA sequencing of 22,969 cells isolated from normal mouse TGs. We identified 18 distinct cell populations, including 6 neuron subpopulations, 3 glial subpopulations, 7 immune cell subpopulations, fibroblasts, and endothelial cells. We also revealed the transcriptional features of genes associated with purinergic signaling, including purinergic receptors, extracellular adenosine triphosphate (eATP) release channels, eATP metabolism-associated enzymes, and eATP transporters in each cell type. Our results have important implications for understanding and predicting the cell type-specific roles of the purinergic signaling in orofacial signal processing in the trigeminal primary sensory system.

show abstract

“…For example, transgenic mouse models with labelled proteins or optimized mass spectrometry could be used [33]. While localizing mRNA can only suggest the presence of functional protein, not confirm it, modern sophisticated RNA-based approaches such as spatial fluorescence in-situ hybridization or single-cell sequencing are increasingly used and can provide evidence for expression at a cellular resolution [36,59,60]. Similarly, pharmacological and functional studies using specific ligands can also help tease apart the contributions of each CGRP family receptor to migraine biology [2].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale

Hendrikse

Rees

Tasma

et al. 2022

IJMS

View full text Add to dashboard Cite

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools. We profiled antibodies for immunodetection of RAMP1 using Western blotting, immunocytochemistry and immunohistochemistry, including using RAMP1 knockout mouse tissue. Most antibodies could detect RAMP1 in Western blotting and immunocytochemistry using transfected cells. Two antibodies (844, ab256575) could detect a RAMP1-like band in Western blots of rodent brain but not RAMP1 knockout mice. However, cross-reactivity with other proteins was evident for all antibodies. This cross-reactivity prevented clear conclusions about RAMP1 anatomical localization, as each antibody detected a distinct pattern of immunoreactivity in rodent brain. We cannot confidently attribute immunoreactivity produced by RAMP1 antibodies (including 844) to the presence of RAMP1 protein in immunohistochemical applications in brain tissue. RAMP1 expression in brain and other tissues therefore needs to be revisited using RAMP1 antibodies that have been comprehensively validated using multiple strategies to establish multiple lines of convincing evidence. As RAMP1 is important for other GPCR/ligand pairings, our results have broader significance beyond the CGRP field.

show abstract

Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine

Cited by 82 publications

References 85 publications

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons

Single-cell RNA sequencing reveals distinct transcriptional features of the purinergic signaling in mouse trigeminal ganglion

Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale

Contact Info

Product

Resources

About