Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development

Veland, Iben R.; Lindbæk, Louise; Christensen, Søren T.

doi:10.1093/biosci/biu179

Cited by 40 publications

(60 citation statements)

References 79 publications

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“…The PC is often considered as a signaling hub and signal integrator, with paramount importance for Shh signaling (Bangs and Anderson, 2017;Baudoin et al, 2012). However, the mechanisms by which cilium-mediated signaling is converted into a migratory response are not well understood (Veland et al, 2014). Our data suggest that the PC forms a single signaling unit with the centrosome, where ciliary AC3 produces cAMP, which concentrates in the PC and diffuses to the centrosome, locally activating PKA.…”

Section: Pc and Neuronal Migrationmentioning

confidence: 73%

“…The PC is often considered as a signal integrator, with paramount importance for Shh signaling (2,21). However, the mechanisms by which cilium-mediated signaling is converted into a migratory response are not understood (22). Our data provide such an intracellular mechanism, whereby the centrosome acts as a cAMP/PKA signaling platform downstream of the PC, with AC3produced cAMP reaching the centrosome, where it locally activates PKA to regulate centrosome dynamics and NK.…”

mentioning

confidence: 77%

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Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Stoufflet

Chaulet

Doulazmi

et al. 2019

Preprint

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The primary cilium (PC) is crucial for neuronal migration but the underlying cellular mechanisms are mostly unknown. Here, we show that ciliary-produced cAMP present at the centrosome locally activates cAMP-dependent Protein Kinase A (PKA). We analyzed cAMP dynamics through biosensor live-imaging in cyclic saltatory migrating neurons of the mouse postnatal rostral migratory stream. This revealed a dynamic cAMP hotspot cyclically present at the centrosome, thus located at the basis of the PC. Genetic ablation of the PC and knockdown of the ciliary Adenylate Cyclase 3 lead to the hotspot disappearance. They also affect migration with defective centrosome/nucleus coupling leading to altered nucleokinesis, which is recapitulated by PKA genetic delocalization. We thus show that PC and centrosome act as a single signaling unit, linked by ciliary cAMP diffusion regulating the rhythmicity of saltatory migration at the centrosome. We generalized this finding to embryonic and adult migrating neurons.

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Section: Pc and Neuronal Migrationmentioning

confidence: 73%

mentioning

confidence: 77%

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Stoufflet

Chaulet

Doulazmi

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The clinical phenotypes observed in ciliopathies are highly heterogeneous, even in the same syndrome, depending on the organ system in which primary cilia are impaired [14] and the mutation state of the individual patient. [15,19,22] A primary cilium can express various receptors for growth factors and morphogens. [209][210][211] In addition, complex crosstalk between various growth factor and morphogen signaling pathways through primary cilia occurs.…”

Section: Future Directionsmentioning

confidence: 99%

Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

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“…Thus, primary cilia have two diverged classes of function: to serve as the "cell antenna" [2,7] to detect extracellular signals and to function as the "keeper of the key for cell division" [3] to regulate mitosis. In accordance, primary cilia play critical roles in sensory perception, and detection of neurotransmitters and hormones, regulation of cell division, development, and tissue regeneration [8][9][10][11]. Currently, little is known about the physiological and pathological function of neuronal and astrocytic primary cilia, despite their strong association with many human diseases including cognitive impairment [12], obesity [13], developmental disorders [14], and glioblastomas [15,16].…”

Section: Introductionmentioning

confidence: 99%

Diverged morphology changes of astrocytic and neuronal primary cilia under reactive insults

et al. 2020

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Primary cilia are centriole-derived sensory organelles that are present in most mammalian cells, including astrocytes and neurons. Evidence is emerging that astrocyte and neuronal primary cilia demonstrate a dichotomy in the mature mouse brain. However, it is unknown how astrocytic and neuronal primary cilia change their morphology and ciliary proteins when exposed to reactive insults including epilepsy and traumatic brain injury. We used a double transgenic mouse strain (Arl13b-mCherry; Centrin2-GFP), in which we found spontaneous seizures, and a cortical injury model to examine the morphological changes of astrocytic and neuronal primary cilia under reactive conditions. Transgenic overexpression of Arl13b drastically increases the length of astrocytic and neuronal primary cilia in the hippocampus, as well as the cilia lengths of cultured astrocytes and neurons. Spontaneous seizures shorten Arl13b-positive astrocytic cilia and AC3-positive neuronal cilia in the hippocampus. In a cortical injury model, Arl13b is not detectable in primary cilia, but Arl13b protein relocates to the cell body and has robust expression in the proximity of injured tissues. In contrast, the number of AC3-positive cilia near injured tissues remains unchanged, but their lengths become shorter. These results on astrocytic cilia implicate Arl13b in regulating astrocyte proliferation and tissue regeneration, while the shortening of AC3-positive cilia suggests adaptive changes of neuronal primary cilia under excitotoxicity.

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Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development

Cited by 40 publications

References 79 publications

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Primary Cilia as Signaling Hubs in Health and Disease

Diverged morphology changes of astrocytic and neuronal primary cilia under reactive insults

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