The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism

Jacobshagen, Moritz; Niquille, Mathieu; Chaumont‐Dubel, Séverine; Marin, Philippe; Dayer, Alexandre

doi:10.1242/jcs.161604

Cited by 9 publications

(32 citation statements)

References 31 publications

(44 reference statements)

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“…Additionally, since the culture media was not dialyzed, residual 5-HT present in the culture medium could have contributed to cAMP production by WT 5-HT6R and 5- HT6R at different developmental stages considering that this receptor has tremendous impacts on cell migration and maturation (Jacobshagen, Niquille, Chaumont-Dubel, et al, 2014). Cultured wild-type neurons will express 5-HT6R throughout in vitro development, while in the present study 5-HT6R was only present in 5-HT6-KO neurons from DIV7-10.…”

Section: Discussionmentioning

confidence: 99%

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Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

et al. 2018

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receptors increases the likelihood for receptors to localize outside of the primary cilium and have been associated with changes in cilia morphology and dendritic outgrowth. In the present study, we explore the role of 5-HT6R rescue on neuronal morphology in primary neuronal cultures from 5-HT6R-KO mice, while maintaining a more physiological level of expression, wherein the receptor localizes to cilia in 80-90% of neurons (similar to endogenous 5-HT6R localization). We found that rescue of 5-HT6R expression is sufficient to increase cilia length and dendritic outgrowth, but primarily in neurons in which the receptor is located exclusively in the primary cilia. Additionally, we found that expression of 5-HT6R mutants, deficient in agonist-stimulated cAMP or without the predicted Fyn kinase binding domain, maintain constitutive activity for stimulating cAMP and still increased the length of cilia, while the proposed Fyn kinase domain was required for stimulating dendritic outgrowth. These findings highlight the complexity of 5-HT6R function and localization, particularly when using exogenous overexpression, and provide greater understanding and potential mechanisms for 5-HT6R drug therapies.

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Section: Discussionmentioning

confidence: 99%

“…The 5-HT6R has extensive constitutive activity (Boess et al, 2002;Jacobshagen, Niquille, and Chaumont-Dubel, 2014;Nadim et al, 2016); therefore, we generated and tested a previously described mutant receptor that is insensitive to 5-HT and other 5-HT6R…”

Section: Ha-5-ht6r Mutant Receptor Generationmentioning

confidence: 99%

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

et al. 2018

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“…The 5-HT 6 receptor also recruits the mammalian Target of Rapamycin (mTOR) Complex 1, and receptor-operated activation of mTOR signaling in prefrontal cortex (PFC) mediates its deleterious influence on cognition (12). Furthermore, 5-HT 6 receptors associate with and activate Cyclin-dependent kinase 5 (Cdk5) in an agonist-independent manner through mechanisms involving receptor phosphorylation by associated Cdk5 to promote migration of neurons and neurite growth (13,14).…”

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confidence: 99%

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Nadim

Chaumont‐Dubel

Madouri

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT 6 ) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the RasGTPase activating protein (Ras-GAP) neurofibromin, a 5-HT 6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT 6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT 6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT 6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1 +/− mice compared with WT mice. Moreover, systemic administration of a 5-HT 6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1 +/− mice. Collectively, these findings suggest that disrupting 5-HT 6 receptor-neurofibromin interaction prevents agonist-independent 5-HT 6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.5-HT 6 receptor | constitutive activity | G protein-coupled receptor | neurofibromin | neurofibromatosis type 1

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“…Dissected brains were fixed, stored in a cryoprotective solution if required, and processed for immunohistochemistry as described previously (22,36) and for proximity ligation assay (PLA) as described in Trifilieff et al (37) with Duolink reagents (Sigma-Aldrich, St. Louis, MO).…”

Section: Tissue Processing Immunohistochemistry and Proximity Ligatmentioning

confidence: 99%

“…The fine positioning of PNs relies on an ultimate migratory step defined as final translocation (19). The precisely orchestrated migration of PNs appears to be a vulnerable cellular process that is affected by different types of psychiatric-related genetic insults (20)(21)(22).…”

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The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis

Molinard-Chenu

Dayer

2018

Biological Psychiatry

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Overall, this study provides biological evidence that the SZ-risk gene DGCR2 regulates critical steps of early corticogenesis possibly through a Reelin-dependent mechanism. Additionally, we found that the SZ-risk mutation in DGCR2 has a pathogenic impact on cortical formation by reducing protein expression level, suggesting a functional role for DGCR2 haploinsufficiency in the 22q11.2 deletion syndrome.

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The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism

Cited by 9 publications

References 31 publications

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis

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The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism

Cited by 9 publications

References 31 publications

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis

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Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Restoration of Physiological Expression of 5-HT₆ Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity