Abstract
A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axon Initial Segment / metabolism*
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Axon Initial Segment / ultrastructure
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Calcium / metabolism*
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Calcium Signaling*
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Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism
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Cell Communication
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Cell Differentiation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian
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Gene Expression Regulation, Developmental
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Hippocampus / cytology
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Hippocampus / growth & development
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Hippocampus / metabolism
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Mice
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Mice, Inbred ICR
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Nerve Growth Factors / pharmacology
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Neurites / metabolism*
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Neurites / ultrastructure
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Neurogenesis / genetics
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Optical Imaging
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Optogenetics
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Primary Cell Culture
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Protein Transport
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Rho Guanine Nucleotide Exchange Factors / genetics
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Rho Guanine Nucleotide Exchange Factors / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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rho GTP-Binding Proteins / genetics*
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rho GTP-Binding Proteins / metabolism
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rhoA GTP-Binding Protein
Substances
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Arhgef2 protein, mouse
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DNA-Binding Proteins
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GLUT4 enhancer factor, mouse
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Nerve Growth Factors
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Rho Guanine Nucleotide Exchange Factors
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Transcription Factors
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neurotropin 3, mouse
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Calcium-Calmodulin-Dependent Protein Kinase Type 1
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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Calcium