Cytoskeleton-related regulation of primary cilia shortening mediated by melanin-concentrating hormone receptor 1

Tomoshige, Sakura; Kobayashi, Yuki; Hosoba, Kosuke; Hamamoto, Akie; Miyamoto, Tatsuo; Saito, Yumiko

doi:10.1016/j.ygcen.2017.08.021

Cited by 23 publications

(16 citation statements)

References 36 publications

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“…Several GPCRs preferentially localize to primary cilia of neurons throughout the brain, including Mchr1 (Berbari et al, 2008b; Hamamoto et al, 2016; Tomoshige et al, 2017). We observe Mchr1 colocalizing with the cilia marker ACIII (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

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Hedgehog Pathway Activation Alters Ciliary Signaling in Primary Hypothalamic Cultures

Bansal

Engle

Antonellis

et al. 2019

Front. Cell. Neurosci.

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Primary cilia dysfunction has been associated with hyperphagia and obesity in both ciliopathy patients and mouse models of cilia perturbation. Neurons throughout the brain possess these solitary cellular appendages, including in the feeding centers of the hypothalamus. Several cell biology questions associated with primary neuronal cilia signaling are challenging to address in vivo . Here we utilize primary hypothalamic neuronal cultures to study ciliary signaling in relevant cell types. Importantly, these cultures contain neuronal populations critical for appetite and satiety such as pro-opiomelanocortin (POMC) and agouti related peptide (AgRP) expressing neurons and are thus useful for studying signaling involved in feeding behavior. Correspondingly, these cultured neurons also display electrophysiological activity and respond to both local and peripheral signals that act on the hypothalamus to influence feeding behaviors, such as leptin and melanin concentrating hormone (MCH). Interestingly, we found that cilia mediated hedgehog signaling, generally associated with developmental processes, can influence ciliary GPCR signaling (Mchr1) in terminally differentiated neurons. Specifically, pharmacological activation of the hedgehog-signaling pathway using the smoothened agonist, SAG, attenuated the ability of neurons to respond to ligands (MCH) of ciliary GPCRs. Understanding how the hedgehog pathway influences cilia GPCR signaling in terminally differentiated neurons could reveal the molecular mechanisms associated with clinical features of ciliopathies, such as hyperphagia-associated obesity.

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Section: Resultsmentioning

confidence: 99%

“…We next assessed if SAG treatment could impact cilia length or electrophysiological activity. Published data suggests that alterations in neuronal cilia length can influence their ability to signal (Besschetnova et al, 2010; Tomoshige et al, 2017). However, we did not observe cilia length changes with SAG treatment (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

Hedgehog Pathway Activation Alters Ciliary Signaling in Primary Hypothalamic Cultures

Bansal

Engle

Antonellis

et al. 2019

Front. Cell. Neurosci.

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“…Hamamoto et al . 45 reported that AKT phosphorylation is an important stage in melanin-concentrating hormone (MCH)-induced cilia length shortening in RPE cells 45,46 . Treatment with LY294002 and wortmannin, inhibitors of phosphoinositide 3-kinase (PI3K), which is an upstream AKT activator, significantly blocked MCH-induced cilia shortening.…”

Section: Discussionmentioning

confidence: 99%

Fine particulate matter (PM2.5) inhibits ciliogenesis by increasing SPRR3 expression via c-Jun activation in RPE cells and skin keratinocytes

Bae

Choi

Shin

et al. 2019

Sci Rep

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Exposure to fine particulate matter (PM) with diameter <2.5 µm (PM2.5) causes epithelium injury and endothelial dysfunction. Primary cilia are sensory organelles that transmit extracellular signals into intracellular biochemical responses and have roles in physiology. To date, there have been no studies investigating whether PM2.5 affects primary cilia in skin. We addressed this in the present study using normal human epidermal keratinocytes (NHEKs) and retinal pigment epithelium (RPE) cells. We found that formation of primary cilium is increased in differentiated NHEKs. However, treatment with PM2.5 blocked increased ciliogenesis in NHEKs and RPE cells. Furthermore, PM2.5 transcriptionally upregulated small proline rich protein 3 (SPRR3) expression by activating c-Jun, and ectopic expression of SPRR3 inhibits suppressed the ciliogenesis. Accordingly, treatment with c-Jun activator (anisomycin) induced SPRR3 expression, whereas the inhibitor (SP600125) recovered the ciliated cells and cilium length in PM2.5-treated cells. Moreover, c-Jun inhibitor suppressed upregulation of SPRR3 in PM2.5-treated cells. Taken together, our finding suggested that PM2.5 inhibits ciliogenesis by increasing SPRR3 expression via c-Jun activation in RPE cells and keratinocytes.

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“…The first hint that the subcellular localization of MCHR1 may be important for its function came in the work of Berbari, Johnson, Lewis, Askwith, and Mykytyn (2008), who described MCHR1 immunoreactivity in the primary cilia of cultured cells, and in a few areas of the central nervous system. After this initial description, a substantial body of studies has developed (Berbari, Lewis, Bishop, Askwith, & Mykytyn, 2008; Green, Gu, & Mykytyn, 2012; Sun et al., 2012; Tomoshige et al., 2017). Primary cilia are nonmotile organelles, formed by microtubules organized in a 9+0 arrangement and covered by a ciliary membrane containing a subset of receptors and proteins that localize to the cilium (Brailov et al., 2000; Händel et al., 1999; Koemeter‐Cox et al, 2014; Loktev & Jackson, 2013; Siljee et al., 2018; Satir, Pedersen, & Christensen, 2010).…”

Section: Introductionmentioning

confidence: 99%

Ciliary melanin‐concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex‐independent manner

Diniz

Battagello

Klein

et al. 2020

J of Neuroscience Research

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Melanin‐concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein‐coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a subcellular structure called the primary cilium, which has been associated, among other functions, with the detection of free neurochemical messengers present in the extracellular space. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, midbrain areas, and in the spinal cord. No differences were observed between male and female mice, and interspecies differences were found in the caudate‐putamen nucleus and the subgranular zone. Ciliary MCHR1 was found in close association with several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin‐releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicate that nonsynaptic communication plays a prominent role in the normal function of the MCH system.

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Cytoskeleton-related regulation of primary cilia shortening mediated by melanin-concentrating hormone receptor 1

Cited by 23 publications

References 36 publications

Hedgehog Pathway Activation Alters Ciliary Signaling in Primary Hypothalamic Cultures

Hedgehog Pathway Activation Alters Ciliary Signaling in Primary Hypothalamic Cultures

Fine particulate matter (PM2.5) inhibits ciliogenesis by increasing SPRR3 expression via c-Jun activation in RPE cells and skin keratinocytes

Ciliary melanin‐concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex‐independent manner

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