Cilia function is associated with axon initial segment morphology

Wang, Bingjie; Hu, Lili; Sun, Zehui; Zhang, Yan

doi:10.1016/j.bbrc.2019.05.172

Cited by 11 publications

(3 citation statements)

References 28 publications

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“…Mounting evidence, however, suggests ciliary length is also relevant in physiological conditions, as spatially-restricted ciliary shortening is observed in obese BBS4-, leptin-, and leptin receptor-deficient mice (21,22). Therefore, studies on cilia length regulation might reveal essential determinants of energy homeostasis linked to obesity in individuals with ciliopathies, as well as other neuronal functions at the cellular level (23,24). Physiological modulation of ciliary length is achieved through multiple soluble factors, including leptin, lysophosphatidic acid, prostaglandin and lithium (25)(26)(27)(28)(29).…”

Section: Accepted Articlementioning

confidence: 99%

Ciliary GPCR‐based transcriptome as a key regulator of cilia length control

et al. 2021

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The primary cilium is a plasma membrane-protruding sensory organelle that efficiently conveys signaling cascades in a highly ordered microenvironment. Its signaling is mediated, in part, by a limited set of GPCRs preferentially enriched in the cilium membrane. This includes melanin-concentrating hormone (MCH) receptor 1 (MCHR1), which plays a role in feeding and mood. In addition to its receptor composition, the length of the cilium is a characteristic parameter that is implicated in its function. We previously found that MCH can dynamically shorten cilia length via the Gi/o and Akt pathways in both MCHR1-expressing hTERT-RPE1 cells (hRPE1 cells) and rat hippocampal neurons. However, the detailed mechanisms by which MCH regulates cilia length through ciliary MCHR1 remains unclear. In this study, we aimed to determine the transcriptome changes in MCHR1-expressing hRPE1 cells in response to MCH to identify the target molecules involved in cilia length regulation via MCHR1 activation. RNA-sequencing analysis of ciliated cells subjected to MCH treatment showed upregulation of 424 genes and downregulation of 112 genes compared with static control cells. Validation by quantitative real-time PCR, knocking down, and CRISPR/Cas9-mediated knockout technology identified a molecule, PDZ and LIM domain-containing protein 5 (PDLIM5). Thus, it was considered as the most significant key factor for MCHR1-mediated shortening of cilia length. Additional analyses revealed that the actin-binding protein alpha-actinin 1/4 is a crucial downstream target of the PDLIM5 signaling pathway that exerts an effect on MCHR1-induced cilia shortening. In the endogenous MCHR1-expressing hippocampus, transcriptional upregulation of PDLIM5 and actinin 1/4, following the application of MCH, was detected when the MCHR1-positive cilia were shortened. Together, our transcriptome study based on ciliary MCHR1 function uncovered a novel and important regulatory step underlying cilia length control. These results will potentially serve as a basis for understanding the mechanism underlying the development of obesity and mood disorders.

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Section: Accepted Articlementioning

confidence: 99%

Ciliary GPCR‐based transcriptome as a key regulator of cilia length control

et al. 2021

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“…In tissue culture studies, the commonly used proteins for cilia labelling are ARL13b and serotonin receptor 6 (5HT 6 ). ARL13b, a member of the ADP-ribosylation factor-like family, is a GTPase protein that anchors the ciliary membrane and plays an important role in controlling ciliary trafficking [15][16][17][18][19], whereas 5HT 6 is a member of the G-protein-coupled receptor (GPCR) family and functions in regulating cilia length, dendritic morphology and cilia protein localization [20][21][22][23]. In the absence of short ciliary targeting sequences, C terminal fusions of their full-length forms to fluorescent proteins have been used for cilia labelling.…”

Section: Introductionmentioning

confidence: 99%

A transgenic zebrafish forin vivovisualization of cilia

Zhang

Huang

et al. 2022

Open Biol.

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Cilia are organelles for cellular signalling and motility. Mutations affecting ciliary function are also associated with cilia-related disorders (ciliopathies). The identification of cilia markers is critical for studying their function at the cellular level. Due to the lack of a conserved, short ciliary localization motif, the full-length ARL13b or 5HT 6 proteins are normally used for cilia labelling. Overexpression of these genes, however, can affect the function of cilia, leading to artefacts in cilia studies. Here, we show that Nephrocystin-3 (Nphp3) is highly conserved among vertebrates and demonstrate that the N-terminal truncated peptide of zebrafish Nphp3 can be used as a gratuitous cilia-specific marker. To visualize the dynamics of cilia in vivo , we generated a stable transgenic zebrafish Tg ( β-actin : nphp3N-mCherry ) sx1001 . The cilia in multiple cell types are efficiently labelled by the encoded fusion protein from embryonic stages to adulthood, without any developmental and physiological defects. We show that the line allows live imaging of ciliary dynamics and trafficking of cilia proteins, such as Kif7 and Smo, key regulators of the Hedgehog signalling pathway. Thus, we have generated an effective new tool for in vivo cilia studies that will help shed further light on the roles of these important organelles.

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“…HTR6 signals through G s proteins and adenylyl cyclase (AC) to promote cAMP synthesis, but it can also stimulate CDK5 and mTOR kinases, among others [15,[26][27][28][29]. Through its multiple interactors and downstream effectors, HTR6 controls neuronal migration and morphogenesis, affecting axonal and dendritic morphology, as well as ciliary length, shape, and composition [15,24,27,28,[30][31][32][33]. For an excellent review on HTR6's interactome, signaling networks and cellular and pathophysiological functions, see [15].…”

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confidence: 99%

HTR6 and SSTR3 targeting to primary cilia

Barbeito

Garcia-Gonzalo

2021

Biochemical Society Transactions

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Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.

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Cilia function is associated with axon initial segment morphology

Cited by 11 publications

References 28 publications

Ciliary GPCR‐based transcriptome as a key regulator of cilia length control

Ciliary GPCR‐based transcriptome as a key regulator of cilia length control

A transgenic zebrafish forin vivovisualization of cilia

HTR6 and SSTR3 targeting to primary cilia

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