Contactins in the neurobiology of autism

Zuko, Amila; Kleijer, Kristel T E; Oguro-Ando, Asami; Kas, Martien; Daalen, Emma van; Zwaag, Bert van der; Burbach, J. Peter H.

doi:10.1016/j.ejphar.2013.07.016

Cited by 94 publications

(96 citation statements)

References 88 publications

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“…Mutations in Contactin family members were identified in patients diagnosed with autism spectrum disorders (Zuko et al, 2013). NrCAM was not only linked to autism but also to a changed behavior in tests for addiction in animals (Sakurai, 2012).…”

Section: Syncams As Axon Guidance Molecules In the Pnsmentioning

confidence: 99%

SynCAMs – From axon guidance to neurodevelopmental disorders

Frei

Stoeckli

2017

Molecular and Cellular Neuroscience

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Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation. They also contribute to myelination by mediating axon-glia cell contacts. More recently, their role in earlier stages of neural circuit formation was demonstrated, as they also guide axons both in the peripheral and in the central nervous system. Mutations in SynCAM genes were found in patients diagnosed with autism spectrum disorders. The diverse functions of SynCAMs during development suggest that neurodevelopmental disorders are not only due to defects in synaptic plasticity. Rather, early steps of neural circuit formation are likely to contribute. Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation. They also contribute to myelination by mediating axon-glia cell contacts. More recently, their role in earlier stages of neural circuit formation was demonstrated, as they also guide axons both in the peripheral and in the central nervous system. Mutations in SynCAM genes were found in patients diagnosed with autism spectrum disorders. The diverse functions of SynCAMs during development suggest that neurodevelopmental disorders are not only due to defects in synaptic plasticity. Rather, early steps of neural circuit formation are likely to contribute.

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Section: Syncams As Axon Guidance Molecules In the Pnsmentioning

confidence: 99%

SynCAMs – From axon guidance to neurodevelopmental disorders

Frei

Stoeckli

2017

Molecular and Cellular Neuroscience

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“…Therefore, the present data suggests that the interactions involve other, partly unknown proteins. Several partners of Cntn6 have been described in literature, 7 but lack functional evidence so far. Increasing evidence indicate that other Cntns engage adhesive trans-interactions, for example the role of Cntn2 in the construction of the node of Ranvier, 40 and a role in signaling by cis-interaction, for example by the heterodimeric Cntn4-APP complex.…”

Section: Discussionmentioning

confidence: 99%

“…The Cntn family consists of six members which are extracellularly attached on the cell surface by a glycosylphosphatidylinositol link (GPI), and contain six Ig and four fibronecin type III domains (FNIII). 6,7 CNTN6 is of particular interest, since studies have indicated that copy number variants in this gene contribute to several neuropsychiatric disorders. [8][9][10][11][12][13][14] This indicates that CNTN6 proteins exert functions that are required for normal neurodevelopment.…”

Section: Introductionmentioning

confidence: 99%

Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus

Zuko

Oguro-Ando

et al. 2016

Cell Adhesion & Migration

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The gene encoding the neural cell adhesion molecule Contactin-6 (Cntn6 a.k.a. NB-3) has been implicated as an autism risk gene, suggesting that its mutation is deleterious to brain development. Due to its GPI-anchor at Cntn6 may exert cell adhesion/receptor functions in complex with other membrane proteins, or serve as a ligand. We aimed to uncover novel phenotypes related to Cntn6 functions during development in the cerebral cortex of adult Cntn6 ¡/¡ mice. We first determined Cntn6 protein and mRNA expression in the cortex, thalamic nuclei and the hippocampus at P14, which decreased specifically in the cortex at adult stages. Neuroanatomical analysis demonstrated a significant decrease of Cux1C projection neurons in layers II-IV and an increase of FoxP2C projection neurons in layer VI in the visual cortex of adult Cntn6 ¡/¡ mice compared to wild-type controls. Furthermore, the number of parvalbuminC (PV) interneurons was decreased in Cntn6 ¡/¡ mice, while the amount of NPYC interneurons remained unchanged. In the hippocampus the delineation and outgrowth of mossy fibers remained largely unchanged, except for the observation of a larger suprapyramidal bundle. The observed abnormalities in the cerebral cortex and hippocampus of Cntn6 ¡/¡ mice suggests that Cntn6 serves developmental functions involving cell survival, migration and fasciculation. Furthermore, these data suggest that Cntn6 engages in both trans-and cis-interactions and may be involved in larger protein interaction networks.

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“…Ген Cntn5 входит в суперсемейство иммуноглобулинов, отвечающих за клеточное взаимодействие (Ogawa et al, 1996;Zuko et al, 2013). Характерной чертой контактинов является большой размер -порядка 1.2 M bp в случае Cntn5.…”

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“…Данные, опублико-ванные этой группой ученых, характеризуют влияние нокаута на деятельность нервной системы, в частности на формирование слуховой системы (Li et al, 2003). Пси-хоневрологические эффекты генов контактинов находят подтверждение в популяционных исследованиях, которые показывают, что у людей полиморфизмы данной группы генов, включая и Cntn5, ассоциируются с расстройствами аутистического спектра (Fernandez et al, 2008;Morrow et al, 2008;Burbach, van der Zwaag, 2009;Roohi et al, 2009;Van Daalen et al, 2011;Zuko et al, 2011Zuko et al, , 2013Nava et al, 2013), с дефицитом внимания и гиперреактивностью (Lionel et al, 2011), нервной анорексией (Nakabayashi et al, 2009).…”

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Morphophysiological alterations caused by insertional mutagenesis of contactin 5 (Cntn5) gene in transgenic mice

Смирнов¹,

Феофанова²,

Концевая³

et al. 2016

Vestn. VOGiS

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Transgenesis has become a routine for modern biolo gical studies. The most popular method for producing transgenic animals-pronuclear microinjection-fre quently leads to host gene disruption due to a random transgene integration. In this paper, we report our analysis of morphophysiological parameters of the transgenic mouse line GM9, in which a transgene designed for milkspecific expression of the human granulocytemacrophage colonystimulating factor (GMCSF) gene was integrated into the intron of the Contactin 5 gene (Cntn5). We studied Cntn5 expres sion with RTPCR and discovered that its expres sion in the brain, the primary organ of Cntn5 activity, was unperturbed. However, transgenic animals had less Cntn5 transcripts in other tissues such as the kidney and heart. In addition, we observed a decreased amount of splice variants of Cntn5 exons that flank the transgene integration site. These data suggest that the transgene integration event might affect proper Cntn5 splicing in some tissues. Publications exist that imply that some polymorphisms in the Cntn5 gene are associated with obesity and arterial hypertension in humans. We evaluated core parameters of lipid metabolism and heart activity in mice homozygous and heterozygous for Cntn5 mutation using wild type animals as control. Our results uncovered that homo zygous mutant mice have lower body weight than controls and that it is caused by slower accumulation of fat tissue. Cntn5 mutants also exhibit abnormalities in blood circulation: homozygous Cntn5 mutants are Технологии трансгенеза активно применяется в самых разных областях биологических исследований. Наиболее активно исполь зуемая методика получения трансгенных животных с помощью инъекции ДНК в пронуклеус зиготы может сопровождаться нару шением функции генов в месте интеграции трансгенной конструк ции. В данной работе описаны морфофизиологические эффекты интеграции трансгенной конструкции, обеспечивающей наработку гранулоцитмакрофаг колониестимулирующего фактора человека в молоко в линии мышей (GM9), встройка конструкции у которых произошла в интрон гена контактин 5 (Cntn5). Было показано, что инсерция конструкции не привела к нокауту Cntn5. Однако у трансгенных животных изменяется транскрипция гена в сердце и почках по сравнению с животными дикого типа, а также меняется спектр транскриптов, что может свидетельствовать о нарушении регуляции сплайсинга гена Cntn5. Из литературных данных извест но, что полиморфизмы Cntn5 ассоциированы со склонностью к ожирению и с предрасположенностью к артериальной гипертен зии. Мы исследовали основные параметры жирового обмена и сердечно сосудистой деятельности у мышей, гомозиготных по инсерции трансгена в ген Cntn5, гетерозиготных животных и животных дикого типа. Проведенное фенотипирование показы вает, что гомозиготные мыши имеют меньшую, чем особи дикого типа, массу тела. Причем весовая разница между генотипами определяется не столько отставанием мутантов в развитии ске лета и мышц, образующих в сумме тощую массу, сколько сущест венно меньшим накоплением жира. У иссл...

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Contactins in the neurobiology of autism

Cited by 94 publications

References 88 publications

SynCAMs – From axon guidance to neurodevelopmental disorders

SynCAMs – From axon guidance to neurodevelopmental disorders

Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus

Morphophysiological alterations caused by insertional mutagenesis of contactin 5 (Cntn5) gene in transgenic mice

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