Kidins220/ARMS controls astrocyte calcium signaling and neuron-astrocyte communication.
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ABSTRACT:
SUBMITTER: Jaudon F
PROVIDER: S-EPMC7206051 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In order for neurons to perform their function, they must establish a highly polarized morphology characterized, in most of the cases, by a single axon and multiple dendrites. Herein we find that the evolutionarily conserved protein Kidins220 (kinase D-interacting substrate of 220-kDa), also known as ARMS (ankyrin repeat-rich membrane spanning), a downstream effector of protein kinase D and neurotrophin and ephrin receptors, regulates the establishment of neuronal polarity and development of dendrites. Kidins220/ARMS gain and loss of function experiments render severe phenotypic changes in the processes extended by hippocampal neurons in culture. Although Kidins220/ARMS early overexpression hinders neuronal development, its down-regulation by RNA interference results in the appearance of multiple longer axon-like extensions as well as aberrant dendritic arbors. We also find that Kidins220/ARMS interacts with tubulin and microtubule-regulating molecules whose role in neuronal morphogenesis is well established (microtubule-associated proteins 1b, 1a, and 2 and two members of the stathmin family). Importantly, neurons where Kidins220/ARMS has been knocked down register changes in the phosphorylation activity of MAP1b and stathmins. Altogether, our results indicate that Kidins220/ARMS is a key modulator of the activity of microtubule-regulating proteins known to actively regulate neuronal morphogenesis and suggest a mechanism by which it contributes to control neuronal development.
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Project description:Astrocytes control the formation of specific synaptic circuits via cell adhesion and secreted molecules. Astrocyte synaptogenic functions are dependent on the establishment of their complex morphology. However, it is unknown if distinct neuronal cues differentially regulate astrocyte morphogenesis. δ-Catenin was previously thought to be a neuron-specific protein that regulates dendrite morphology. We found δ-catenin is also highly expressed by astrocytes and required both in astrocytes and neurons for astrocyte morphogenesis. δ-Catenin is hypothesized to mediate transcellular interactions through the cadherin family of cell adhesion proteins. We used structural modeling and biochemical analyses to reveal that δ-catenin interacts with the N-cadherin juxtamembrane domain to promote N-cadherin surface expression. An autism-linked δ-catenin point mutation impaired N-cadherin cell surface expression and reduced astrocyte complexity. In the developing mouse cortex, only lower-layer cortical neurons express N-cadherin. Remarkably, when we silenced astrocytic N-cadherin throughout the cortex, only lower-layer astrocyte morphology was disrupted. These findings show that δ-catenin controls astrocyte-neuron cadherin interactions that regulate layer-specific astrocyte morphogenesis.
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Project description:Nonsense variants in KIDINS220/ARMS were identified as the main cause of spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome, a rare disease with birth defects in brachycephaly, neurological disorder, and obesity. The cause of neural cell dysfunction by KIDINS220/ARMS were extensively studied while the cause of obesity in SINO syndrome remains elusive. Here, we identified KIDINS220/ARMS as an adipocyte differentiation-regulating gene. A Chinese family, mother and her two sons, all showed severe symptoms of SINO syndrome. G-banding karyotyping, chromosome microarray analysis, and whole exome sequencing revealed a novel amber mutation, c.3934G>T (p. E1312X), which was close to the C-terminal region of KIDINS220/ARMS and resulted in the premature of the protein. Both the mRNA and protein levels of KIDINS220/ARMS gradually decreased during adipocyte differentiation. Knockdown of KINDINS220/ARMS could prompt adipocyte differentiation and lipid accumulation while overexpression of KIDINS220/ARMS decrease the rate of matured adipocytes. Furthermore, we demonstrated that KIDINS220/ARMS inhibits adipocyte maturation through sustained extracellular signal-regulated kinase signaling. In conclusion, this is the first report about a vertical heredity of severe dominant pathogenic mutation of KIDINS220/ARMS, suggested that KIDINS220/ARMS played a negative role in adipocyte maturation, explained the cause of obesity in SINO syndrome and could highlight the importance of adipocyte differentiation in neuron functions.
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Project description:Thy-1 is an abundant neuronal glycoprotein of poorly defined function. We recently provided evidence indicating that Thy-1 clusters a beta3-containing integrin in astrocytes to induce tyrosine phosphorylation, RhoA activation and the formation of focal adhesions and stress fibers. To date, the alpha subunit partner of beta3 integrin in DI TNC1 astrocytes is unknown. Similarly, the ability of neuronal, membrane-bound Thy-1 to trigger astrocyte signaling via integrin engagement remains speculation. Here, evidence that alphav forms an alphavbeta3 heterodimer in DI TNC1 astrocytes was obtained. In neuron-astrocyte association assays, the presence of either anti-alphav or anti-beta3 integrin antibodies reduced cell-cell interaction demonstrating the requirement of both integrin subunits for this association. Moreover, anti-Thy-1 antibodies blocked stimulation of astrocytes by neurons but not the binding of these two cell types. Thus, neuron-astrocyte association involved binding between molecular components in addition to the Thy-1-integrin; however, the signaling events leading to focal adhesion formation in astrocytes depended exclusively on the latter interaction. Additionally, wild-type (RLD) but not mutated (RLE) Thy-1 was shown to directly interact with alphavbeta3 integrin by Surface Plasmon Resonance analysis. This interaction was promoted by divalent cations and was species-independent. Together, these results demonstrate that the alphavbeta3 integrin heterodimer interacts directly with Thy-1 present on neuronal cells to stimulate astrocytes.
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Project description:BackgroundNeurotrophic signaling is an important factor in the survival of developing neurons, and the expression of neurotrophic receptors correlates with prognosis in neuroblastoma. Kinase D-interacting substrate of 220 kDa (Kidins220) associates with neurotrophic receptors and stabilizes them, but the expression and function of Kidins220 in neuroblastoma are unknown.MethodsWe study Kidins220 expression in human neuroblastoma cell lines and tumor samples by western blotting and microarray analyses. We determine the functional consequences of downregulation of Kidins220 for response of cell lines to oxidative stress, chemotherapeutic treatment, and neurotrophins using small interfering RNA silencing and by measuring cell survival, signaling, and migration.ResultsKidins220 is expressed in all neuroblastoma tumors and cell lines studied. Downregulation of Kidins220 leads to attenuation of nerve growth factor (NGF)-induced, but not brain-derived neurotrophic factor (BDNF)-induced, MAPK signaling. However, downregulation of Kidins220 does not alter the response to chemotherapeutic drugs or oxidative stress or affect cellular motility.ConclusionKidins220 is expressed in neuroblastoma tumors and stabilizes NGF-induced, but not BDNF-induced, survival signaling in neuroblastoma cell lines.
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Project description:Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.
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Project description:Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-enriched astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses; conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep-layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.
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