TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly

Jacquemin, Valérie; Antoine, Mathieu; Duerinckx, Sarah; Massart, Annick; Désir, Julie; Perazzolo, Camille; Cassart, Marie; Thomas, D.; Segers, Valérie; Lecomte, Sophie; Abramowicz, Marc; Pirson, Isabelle

doi:10.1093/hmg/ddaa245

Cited by 12 publications

(15 citation statements)

References 52 publications

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“…In this work we laid the basis for understanding SINO syndrome, identifying alterations in the neurotrophic system as one factor contributing to the pathology. Indeed, one pathogenic KIDINS220 variant shows reduced binding to TrkA [ 9 ], suggesting neurotrophin pathways as potential targets for future therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS modulates brain morphology and anxiety-like traits in adult mice

et al. 2022

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Kinase D interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is a transmembrane scaffold protein that participates in fundamental aspects of neuronal physiology including cell survival, differentiation, and synaptic plasticity. The Kidins220 constitutive knockout line displays developmental defects in the nervous and cardiovascular systems that lead to embryonic lethality, which has so far precluded the study of this protein in the adult. Moreover, Kidins220 mRNA is tightly regulated by alternative splicing, whose impact on nervous system physiology has not yet been addressed in vivo. Here, we have asked to what extent the absence of Kidins220 splicing and the selective knockout of Kidins220 impact on adult brain homeostasis. To answer this question, we used a floxed line that expresses only the full-length, non-spliced Kidins220 mRNA, and a forebrain-specific, CaMKII-Cre driven Kidins220 conditional knockout (cKO) line. Kidins220 cKO brains are characterized by enlarged ventricles in the absence of cell death, and by deficient dendritic arborization in several cortical regions. The deletion of Kidins220 leads to behavioral changes, such as reduced anxiety-like traits linked to alterations in TrkB-BDNF signaling and sex-dependent alterations of hippocampal-dependent spatial memory. Kidins220 floxed mice present similarly enlarged brain ventricles and increased associative memory. Thus, both the absolute levels of Kidins220 expression and its splicing pattern are required for the correct brain development and related expression of behavioral phenotypes. These findings are relevant in light of the increasing evidence linking mutations in the human KIDINS220 gene to the onset of severe neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS modulates brain morphology and anxiety-like traits in adult mice

et al. 2022

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“…In future studies we will address how these findings translate in vivo, under physiological and pathological conditions. In recent years, mutations in the KIDINS220 gene have been associated with severe neurodevelopmental pathologies, whose main symptoms are intellectual disability and spastic paraplegia (Cesca et al, 2018;El-Dessouky et al, 2020;Jacquemin et al, 2020;Josifova et al, 2016;Mero et al, 2017;Yang et al, 2018;Zhao et al, 2019). Within this context, the observation that Kidins220 controls astrocyte metabolism during embryonic development is instrumental to tackle the pathogenic mechanisms that underlie Kidins220-dependent neurodevelopmental diseases (i.e.…”

Section: Discussionmentioning

confidence: 99%

A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

Jaudon

Albini

Ferroni

et al. 2021

Journal of Cell Science

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Astroglial cells are key to maintain nervous system homeostasis. Neurotrophins are known for their pleiotropic effects on neuronal physiology, but also exert complex functions onto glial cells. In this work, we investigated: (i) the signaling competence of embryonic and postnatal primary cortical astrocytes exposed to brain-derived neurotrophic factor (BDNF); and (ii) the role of Kinase D interacting substrate (Kidins220), a transmembrane scaffold protein that mediates neurotrophin signaling in neurons, in the astrocyte response to BDNF. We found a shift from a kinase-based response in embryonic cells to a predominantly [Ca2+]i-based response in postnatal cultures associated with the decreased expression of the full-length BDNF receptor TrkB, with a contribution of Kidins220 to the BDNF-activated kinase and [Ca2+]i pathways. Finally, Kidins220 participates in astrocytes’ homeostatic function by controlling the expression of the inwardly rectifying potassium channel (Kir) 4.1 and the metabolic balance of embryonic astrocytes. Overall, our data contribute to the understanding of the complex role played by astrocytes within the central nervous system and identify Kidins220 as a novel actor in the increasing number of pathologies characterized by astrocytic dysfunctions.

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“…Our future studies will address how these findings will translate in vivo, under physiological and pathological conditions. In recent years, mutations in the KIDINS220 gene have been associated with severe neurodevelopmental pathologies, whose main symptoms are intellectual disability and spastic paraplegia (55)(56)(57)(58)(59)(60)(61). A better understanding of the physiological functions of neurotrophins and Kidins220 in neurons and glial cells is instrumental to address the molecular pathways leading to this severe neurological disorder, which are currently completely unknown.…”

Section: Discussionmentioning

confidence: 99%

A developmental stage- and Kidins220/ARMS-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

Jaudon

Albini

Ferroni

et al. 2021

Preprint

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Astroglial cells are key to maintain nervous system homeostasis, as they are able to perceive a wide variety of extracellular signals and to transduce them into responses that may be protective or disruptive toward neighboring neurons through the activation of distinct signaling pathways. Neurotrophins are a family of growth factors known for their pleiotropic effects on neuronal survival, maturation and plasticity. In this work, we investigated: (i) the signaling competence of embryonic and postnatal primary cortical astrocytes exposed to brain-derived neurotrophic factor (BDNF); and (ii) the role of the scaffold protein Kinase D interacting substrate/ankyrin repeat-rich membrane spanning (Kidins220/ARMS), a transmembrane protein that mediates neurotrophin signaling in neurons, in the astrocyte response to BDNF. We found a shift from a kinase-based response in embryonic cells to a predominantly [Ca2+]i-based response in postnatal cultures associated with the decreased expression of the full-length BDNF receptor TrkB. We also found that Kidins220/ARMS contributes to the BDNF-activated intracellular signaling in astrocytes by potentiating both kinase and [Ca2+]i pathways. Finally, Kidins220/ARMS contributes to astrocytes′ homeostatic function by controlling the expression of the inwardly rectifying potassium channel (Kir) 4.1. Overall, our data contribute to the understanding of the complex role played by astrocytes within the central nervous system and identify Kidins220/ARMS as a novel actor in the increasing number of pathologies characterized by astrocytes′ dysfunctions.

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TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly

Cited by 12 publications

References 52 publications

Kidins220/ARMS modulates brain morphology and anxiety-like traits in adult mice

Kidins220/ARMS modulates brain morphology and anxiety-like traits in adult mice

A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

A developmental stage- and Kidins220/ARMS-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

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