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

Stoufflet, Julie; Chaulet, Maxime; Doulazmi, Mohamed; Fouquet, Coralie; Dubacq, Caroline; Métin, Christine; Trembleau, Alain; Vincent, Pierre; Caillé, Isabelle

doi:10.1101/765925

Cited by 7 publications

(9 citation statements)

References 63 publications

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“…Finally, while our data demonstrates that the cilium is involved in the apical nuclear translocation of rod photoreceptors, the precise ciliary signal remains unknown. Cilia have previously been shown to play a role in neuronal nuclear migration, with studies implicating both Arl13B (Higginbotham et al, 2012) and cAMP signaling (Stoufflet et al, 2020). Our study now links Arl3 to nuclear migration and the next step will be to identify the lipidated cargo relying on the ciliary Arl3 gradient within photoreceptors during development.…”

Section: Discussionmentioning

confidence: 99%

Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration

Travis

Manocha

Willer

et al. 2022

Preprint

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The small GTPase Arl3 is important for the enrichment of lipidated proteins to primary cilia, including the outer segment of photoreceptors. Human mutations in the small GTPase Arl3 cause both autosomal recessive and dominant inherited retinal dystrophies. We discovered that dominant mutations result in aberrant activity—Arl3-D67V has constitutively activity and Arl3-Y90C is fast cycling—and expression in mouse rods resulted in a displaced nuclear phenotype, similar to the GTP-locked Q71L mutant. Using multiple strategies, we go on to show that removing or restoring the Arl3-GTP gradient within the cilium is sufficient to rescue the nuclear migration defect. Together, our results reveal that a Arl3 ciliary gradient is involved in proper positioning of photoreceptor nuclei during retinal development.

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Section: Discussionmentioning

confidence: 99%

Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration

Travis

Manocha

Willer

et al. 2022

Preprint

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“…We also document that the reverse movement of late-born neurons from the bottom of SP to the main SP is crucial for the establishment of the laminar structure of hippocampal CA1, which may indirectly affect the maturation or synaptic connectivity of lateborn neurons. immunostaining signal is only detected at centrosomes (94), with limited enrichment at SP bottom. At P9, primary cilia are expressed but very short.…”

Section: Primary Cilium Is Likely To Orient In a Specific Direction To Modulate Early-and Late-born Neurons Positioningmentioning

confidence: 95%

“…At P5, only early-born neurons express north-pointing cilia. At P7, hair-like cilia are hard to be seen in the CA1 and AC3 immunostaining signal is only detected at centrosomes (92), with limited enrichment at SP bottom. At P9, primary cilia are expressed throughout CA1 but very short.…”

Section: Pyramidal Cell Positioning To the Deep And Superficial Sublayers Is Regulated By Centriole Positioning Ciliation Timing And Cilimentioning

confidence: 99%

“…The centriole/centrosome, as the microtubule-organizing center, directs cellular microtubule dynamics that couple to nuclear translocation during individual cell migration (30,33,34,92). Polarized centriole positioning is found to be important for properly oriented cell division, polarized cilia positioning, and cell migration (93).…”

Section: Pyramidal Cell Positioning To the Deep And Superficial Sublayers Is Regulated By Centriole Positioning Ciliation Timing And Cilimentioning

confidence: 99%

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Primary Cilia Directionality Reveals a Slow Reverse Movement of Principal Neurons for Postnatal Positioning and Lamina Refinement in the Cerebral Cortex

Yang

Qiu

Chen

2021

Preprint

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It is well-recognized that primary cilia regulate embryonic neurodevelopment, but little is known about their roles in postnatal neurodevelopment. The striatum pyramidal (SP) of hippocampal CA1 consists of superficial and deep sublayers, however, it is not well understood how early- and late-born pyramidal neurons position to two sublayers postnatally. Here we show that neuronal primary cilia emerge after CA1 pyramidal cells have reached SP, but before final neuronal positioning. The axonemes of primary cilia of early-born neurons point to the stratum oriens (SO), whereas late-born neuronal cilia orient toward the stratum radiatum (SR), reflecting an inside-out lamination pattern. Neuronal primary cilia in SP undergo marked changes in morphology and orientation from postnatal day 5 (P5) to P14, concurrent with pyramidal cell positioning to the deep and superficial sublayers and with neuronal maturation. Transgenic overexpression of Arl13B, a protein regulating ciliogenesis, not only elongates primary cilia and promotes earlier cilia protrusion, but also affects centriole positioning and cilia orientation in SP. The centrioles of late-born neurons migrate excessively to cluster at SP bottom before primary cilia protrusion and a reverse movement back to the main SP. Similarly, this pull-back movement of centriole/cilia is also identified on late-born cortical pyramidal neurons, although early- and late-born cortical neurons display the same cilia orientation. Together, this study provides the first evidence demonstrating that late-born pyramidal neurons exhibit a reverse movement for cell positioning, and primary cilia regulate pyramidal neuronal positioning to the deep and superficial sublayers in the hippocampus.

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“…Ciliary function is very complex with function controlled by cytoplasmic signals as well as direct signals to specific locations on the cilium, e.g., sonic hedgehog-signaling through receptors on the "tip" of the primary cilium. 75,76 Furthermore, Wnt/β-catenin 65,66 and Notch signaling 77 involves interaction with cilia.…”

Section: Hydrocephalus As a Ciliopathymentioning

confidence: 99%

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

Munch

Hedley

Hagen

et al. 2022

Preprint

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Background Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using this data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with autism spectrum disorder, identified in the iPSYCH cohort. Methods One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome sequenced sub cohort of the iPSYCH study, comprising 72 hydrocephalus patients and 4,181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and autism spectrum disorder. Results The median age at diagnosis for the hydrocephalus patients was 0 years of age (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5 % were males. Median age for controls was 18 years (range 11-26 years) and 53.3 % were males. Fifty-two putative hydrocephalus-associated variants in 34 genes, were identified in 42 patients (58.3 %). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (OR 1.51, 95% CI 0.92-2.51, p = 0.096), which was driven by a significant enrichment of rare protein truncating variants (OR 2.71, 95% CI 1.17-5.58, p = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with autism spectrum disorder. Conclusions Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms and identification of co-morbidities may be of clinical significance, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus, but also, brain disease in the broadest sense, given the essential role of cilia for neurodevelopment.

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

Cited by 7 publications

References 63 publications

Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration

Disrupting the ciliary gradient of active Arl3 affects rod photoreceptor nuclear migration

Primary Cilia Directionality Reveals a Slow Reverse Movement of Principal Neurons for Postnatal Positioning and Lamina Refinement in the Cerebral Cortex

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

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