A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility

Sheu, Shu-Hsien; Upadhyayula, Srigokul; Dupuy, Vincent; Pang, Song; Deng, Fei; Wan, Jinxia; Walpita, Deepika; Pasolli, H. Amalia; Houser, Justin R.; Sánchez-Martínez, Silvia; Brauchi, Sebastián; Banala, Sambashiva; Freeman, Melanie; Xu, Chengpei; Kirchhausen, Tom; Hess, Harald F.; Lavis, Luke D.; Li, Yulong; Chaumont‐Dubel, Séverine; Clapham, David E.

doi:10.1016/j.cell.2022.07.026

Cited by 67 publications

(61 citation statements)

References 105 publications

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“…Mice with disrupted D1 ciliary localization have a reduction in D1-mediated signaling in the striatum that is associated with a decrease in locomotor activity and obesity ( Stubbs et al, 2022 ). Recently, synapses between serotonergic axons and primary cilia of hippocampal CA1 neurons have been described in the mouse brain ( Sheu et al, 2022 ). Importantly, serotonin release stimulates ciliary Htr6 and activates a non-canonical signaling pathway to increase chromatin accessibility ( Sheu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, synapses between serotonergic axons and primary cilia of hippocampal CA1 neurons have been described in the mouse brain ( Sheu et al, 2022 ). Importantly, serotonin release stimulates ciliary Htr6 and activates a non-canonical signaling pathway to increase chromatin accessibility ( Sheu et al, 2022 ). Overall, ciliary GPCR signaling appears to be important for normal neuronal function.…”

Section: Introductionmentioning

confidence: 99%

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Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice

Stubbs

Bingman

Besse

et al. 2023

Front. Cell Dev. Biol.

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In the brain, primary cilia are found on most, if not all, central neurons. The importance of neuronal cilia is underscored by the fact that human diseases caused by primary cilia dysfunction, which are known as ciliopathies, are associated with neuropathologies, including neuropsychiatric disorders and learning and memory deficits. Neuronal cilia are enriched for certain G protein-coupled receptors and their downstream effectors, suggesting they sense and respond to neuromodulators in the extracellular milieu. GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet-Biedl syndrome, with GPCRs failing to localize to cilia, indicating the Bardet-Biedl syndrome proteins are required for trafficking of G protein-coupled receptors into neuronal cilia. Yet, dopamine receptor 1 accumulates in cilia in the absence of Bardet-Biedl syndrome proteins, suggesting Bardet-Biedl syndrome proteins are required for normal ciliary import and export. To further explore the roles of the Bardet-Biedl syndrome proteins in neuronal cilia, we examined localization of ciliary signaling proteins in a new constitutive Bbs1 knockout mouse model. Interestingly, we find that two additional ciliary G protein-coupled receptors (Gpr161 and Gpr19) abnormally accumulate in cilia on Bardet-Biedl syndrome neurons. In addition, we find that the GPCR signaling protein β-arrestin accumulates in a subset of cilia in the brain, suggesting the presence of additional unidentified ciliary G protein-coupled receptors. These results confirm the importance of the Bardet-Biedl syndrome proteins in establishing ciliary GPCR pathways and indicate that loss of Bbs1 leads to complex changes in the localization of signaling proteins in the brain.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice

Stubbs

Bingman

Besse

et al. 2023

Front. Cell Dev. Biol.

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“…Simply visualizing cilia in the CNS is a challenge, as the standard tubulin markers are not specific to the organelle in neurons (Caspary et al, 2016). Even fundamental questions around understanding if neuronal cilia act through slower neuropeptide mediated mechanisms or directly influence neuronal activity, as suggested with the observation that cilia can directly synapse to neurons (Sheu et al, 2022), or perhaps cilia serve as both slow and fast modulators of neurons and circuits. Fascinating work in models like C. elegans has suggested that neuronal cilia length changes can directly impact their ability to sense the external environment (Maurya and Sengupta, 2022).…”

Section: Challenges and Future Directions And Conclusionmentioning

confidence: 99%

“…For example, a recent study has proposed the idea of axo-ciliary synapses. Here, they show that artificial stimulation of serotonergic axons releases serotonin directly onto the ciliary receptor 5-hydroxytrptamine receptor 6 (5-HTR6) in hippocampal neurons to activate the Gα q/11 RhoA pathway ( Sheu et al, 2022 ). Further research could elucidate other neuronal populations that may use their cilium to form axo-ciliary synapses to regulate different functions, perhaps those involved in energy homeostasis.…”

Section: Genetic Mouse Models Of Cilia Associated Obesitymentioning

confidence: 99%

Neuronal cilia in energy homeostasis

Brewer

Richardson

et al. 2022

Front. Cell Dev. Biol.

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A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.

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“…It may explain the profound effects of 5-HT-like psychedelics in mental disorders ( Vollenweider and Kometer, 2010 ; Daws et al, 2022 ). Some of these effects may be associated with chromatin remodeling ( Sheu et al, 2022 ). A growing body of literature suggests close associations between plasticity and randomness in other systems ( van der Groen et al, 2022 ; Voortman and Johnston, 2022 ), suggesting that the stochasticity of serotonergic axons may not be an evolutionary accident.…”

Section: Introductionmentioning

confidence: 99%

High-resolution spatiotemporal analysis of single serotonergic axons in an in vitro system

Hingorani

Viviani²,

Sanfilippo³

et al. 2022

Front. Neurosci.

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Vertebrate brains have a dual structure, composed of (i) axons that can be well-captured with graph-theoretical methods and (ii) axons that form a dense matrix in which neurons with precise connections operate. A core part of this matrix is formed by axons (fibers) that store and release 5-hydroxytryptamine (5-HT, serotonin), an ancient neurotransmitter that supports neuroplasticity and has profound implications for mental health. The self-organization of the serotonergic matrix is not well understood, despite recent advances in experimental and theoretical approaches. In particular, individual serotonergic axons produce highly stochastic trajectories, fundamental to the construction of regional fiber densities, but further advances in predictive computer simulations require more accurate experimental information. This study examined single serotonergic axons in culture systems (co-cultures and monolayers), by using a set of complementary high-resolution methods: confocal microscopy, holotomography (refractive index-based live imaging), and super-resolution (STED) microscopy. It shows that serotonergic axon walks in neural tissue may strongly reflect the stochastic geometry of this tissue and it also provides new insights into the morphology and branching properties of serotonergic axons. The proposed experimental platform can support next-generation analyses of the serotonergic matrix, including seamless integration with supercomputing approaches.

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A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility

Cited by 67 publications

References 105 publications

Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice

Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice

Neuronal cilia in energy homeostasis

High-resolution spatiotemporal analysis of single serotonergic axons in an in vitro system

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