Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling–dependent neurogenesis in the embryonic neural tube

Shim, Sangwoo; Goyal, Raman; Πανουτσόπουλος, Αλέξιος; Balashova, Olga A; Lee, David; Borodinsky, Laura N.

doi:10.1073/pnas.2220037120

Cited by 8 publications

(5 citation statements)

References 74 publications

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“…Thus, alternative explanations appear to be required. 69 and neural stem cells 70 , and calcium signaling can propagate rapidly along axons 71,72 , while primary cilia are specialized calcium signaling cellular organelles [73][74][75] . However, the dependence of the function of primary cilia in nociceptor function on short and long range calcium signaling remains to be established.…”

Section: Discussionmentioning

confidence: 99%

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

Tucker,

Fitzsimons,

Staurengo-Ferrari

et al. 2024

Preprint

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The primary cilium, a 1-3 μm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targeting Ift88, a primary cilium-specific intra-flagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss of Ift88 mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E2, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein, Ift52. Ift52 siRNA results in loss of Ift52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia by Ift88 knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.

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Section: Discussionmentioning

confidence: 99%

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

Tucker,

Fitzsimons,

Staurengo-Ferrari

et al. 2024

Preprint

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show abstract

“…Thus, alternative explanations appear to be required. Shh enhances calcium oscillations in embryonic neurons 69 and neural stem cells 70 , and calcium signaling can propagate rapidly along axons 71,72 , while primary cilia are specialized calcium signaling cellular organelles 73–75 . However, the dependence of the function of primary cilia in nociceptor function on short and long range calcium signaling remains to be established.…”

Section: Discussionmentioning

confidence: 99%

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

Fitzsimons,

Staurengo-Ferrari,

Bogen

et al. 2023

Preprint

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The primary cilium, a 1-3 μm long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targetingIft88, a primary cilium-specific intra-flagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss ofIft88mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E2, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein,Ift52.Ift52 siRNA results in loss ofIft52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia byIft88knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.

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“…The Ca 2+ signals are characterised by rapid on- and off-kinetics and are often restricted to ciliary sub-compartments. In other cell types, ciliary Ca 2+ has been shown to negatively regulate cilia length, which may attenuate ciliary sensing abilities, and to directly modulate ciliary receptor signalling [ 32 , 33 ], yet direct evidence that Ca 2+ acts as a rapid second messenger, similar to its function in the cytosol, is lacking. Some clues may come from studies of Ca 2+ signalling in dendritic spines, which are post-synaptic structures that share many properties with primary cilia, including a high surface-to-volume ratio, small size, isolation from the cell body and chemosensory abilities [ 34 ].…”

Section: Coupling Ciliary Receptors To Downstream Signalling Pathwaysmentioning

confidence: 99%

Keeping pace: the primary cilium as the conducting baton of the islet

Idevall-Hagren,

Incedal Nilsson,

Sanchez

2024

Diabetologia

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Primary cilia are rod-like sensory organelles that protrude from the surface of most mammalian cells, including the cells of the islet, and mounting evidence supports important roles of these structures in the regulation of beta cell function and insulin secretion. The sensory abilities of the cilium arise from local receptor activation that is coupled to intrinsic signal transduction, and ciliary signals can propagate into the cell and influence cell function. Here, we review recent advances and studies that provide insights into intra-islet cues that trigger primary cilia signalling; how second messenger signals are generated and propagated within cilia; and how ciliary signalling affects beta cell function. We also discuss the potential involvement of primary cilia and ciliary signalling in the development and progression of type 2 diabetes, identify gaps in our current understanding of islet cell cilia function and provide suggestions on how to further our understanding of this intriguing structure. Graphical Abstract

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Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling–dependent neurogenesis in the embryonic neural tube

Cited by 8 publications

References 74 publications

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

Keeping pace: the primary cilium as the conducting baton of the islet

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