title: Dendritic geometry shapes neuronal cAMP signalling to the nucleus.
abstract: Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. Yet the rules of molecular signal propagation from dendrites to nuclei are unknown. DARPP-32 is a phosphorylation-regulated signalling hub in striatal output neurons. We combine diffusion-reaction modelling and live imaging to investigate cAMP-activated DARPP-32 signalling to the nucleus. The model predicts maximal effects on the nucleus of cAMP production in secondary dendrites, due to segmental decrease of dendrite diameter. Variations in branching, perikaryon size or spines have less pronounced effects. Biosensor kinase activity measurement following cAMP or dopamine uncaging confirms these predictions. Histone 3 phosphorylation, regulated by this pathway, is best stimulated by cAMP released in secondary-like dendrites. Thus, unexpectedly, the efficacy of diffusion-based signalling from dendrites to nucleus is not inversely proportional to the distance. We suggest a general mechanism by which dendritic geometry counterbalances the effect of dendritic distance for signalling to the nucleus.
authors.affiliation: 1] Inserm, UMR-S 839, 75005 Paris, France [2] Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités, 75005 Paris, France [3] Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Lu
authors.identifier: 000000026199522X
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] Inserm, UMR-S 839, 75005 Paris, France [2] Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités, 75005 Paris, France [3] Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gervasi
authors.affiliation: 1] Inserm, UMR-S 839, 75005 Paris, France [2] Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités, 75005 Paris, France [3] Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003342:Corpus Striatum / Q000196:embryology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D004058:Diffusion; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D006657:Histones / Q000737:chemistry; D008027:Light; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D012984:Software
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006657:Histones; C497929:Ppp1r1b protein, mouse; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine