Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice

Schob, Claudia; Morellini, Fabio; Ohana, Ora; Bakota, Lidia; Hrynchak, Mariya V.; Brandt, Roland; Brockmann, Marco D.; Cichon, Nicole; Hartung, Henrike; Hanganu‐Opatz, Ileana L.; Kraus, Vanessa; Scharf, Sarah; Herrmans-Borgmeyer, Irm; Schweizer, Michaela; Kuhl, Dietmar; Wöhr, Markus; Vörckel, Karl Jakob; Calzada‐Wack, Julia; Fuchs, Helmut; Gailus‐Durner, Valérie; Angelis, Martin Hrabé de; Garner, Craig C.; Kreienkamp, Hans‐Jürgen; Kindler, Stefan

doi:10.1038/s41398-018-0327-z

Cited by 15 publications

(17 citation statements)

References 78 publications

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“…For the post-synaptic Dlgap4 linked to neuropsychiatric disorders 52 non-neurons and immature neurons predominantly express one exon. However, during neuronal maturation, exon inclusion switches to both exons (Fig.…”

Section: Resultsmentioning

confidence: 99%

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

et al. 2021

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Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity.

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Section: Resultsmentioning

confidence: 99%

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

et al. 2021

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“…The length of the dendrites and the number of branching points from three different species are shown in the table below. The numbers are based on data from the evaluation of eight fluorescent neurons from the hippocampus of a GFP-expressing mouse line (14-20 weeks old male mice; Schob et al, 2019), 20 horseradish peroxidase injected CA1 neurons from the rat hippocampus (33-57 days old female rats; Ishizuka et al, 1995), and 30 biocytinlabeled CA1 neurons from 11 months to 24-year-old Macaca mulatta and M. fascicularis (Altemus et al, 2005). Mean ± SEM are shown.…”

Section: Introductionmentioning

confidence: 99%

The microtubule skeleton and the evolution of neuronal complexity in vertebrates

Trushina

Mulkidjanian

Brandt

2019

Biological Chemistry

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The evolution of a highly developed nervous system is mirrored by the ability of individual neurons to develop increased morphological complexity. As microtubules (MTs) are crucially involved in neuronal development, we tested the hypothesis that the evolution of complexity is driven by an increasing capacity of the MT system for regulated molecular interactions as it may be implemented by a higher number of molecular players and a greater ability of the individual molecules to interact. We performed bioinformatics analysis on different classes of components of the vertebrate neuronal MT cytoskeleton. We show that the number of orthologs of tubulin structure proteins, MT-binding proteins and tubulin-sequestering proteins expanded during vertebrate evolution. We observed that protein diversity of MT-binding and tubulin-sequestering proteins increased by alternative splicing. In addition, we found that regions of the MT-binding protein tau and MAP6 displayed a clear increase in disorder extent during evolution. The data provide evidence that vertebrate evolution is paralleled by gene expansions, changes in alternative splicing and evolution of coding sequences of components of the MT system. The results suggest that in particular evolutionary changes in tubulin-structure proteins, MT-binding proteins and tubulin-sequestering proteins were prominent drivers for the development of increased neuronal complexity.

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“…Cell Lysis, Immunoprecipitation, Western Blotting, Statistical Methods, and Software Lysis of transfected HEK293T cells, immunopurification of EGFP-tagged recombinant proteins from lysates utilizing GFP-Trap Magnetic Agarose beads (Chromotek), and Western blotting analysis were essentially performed as described. [24][25][26] After blotting, membranes were incubated with the following antibodies: anti-DDX21 rabbit polyclonal antibodies (Bethyl, #A300-627A, A300-628A, and A300-629A), anti-green fluorescent protein mouse monoclonal antibody (Covance, #MMS-118P-200), anti-NCBP1/CBP80 (D7Z2Z) rabbit monoclonal antibody (Cell Signalling, #24964), anti-NCBP2 rabbit polyclonal antibody (Bethyl, #A302-553A), anti-RCC1 rabbit polyclonal antibody (Sigma-Aldrich, #HPA027573), and 2 anti-ataxin-3 antibodies (MyBioSource, #MBS178269; Sigma Aldrich, #HPA069338). Immune complexes were visualized with ECL substrate (ThermoFisher Scientific) and the ChemiDoc XRS+ System (Bio-Rad Laboratories).…”

Section: Expression Plasmidsmentioning

confidence: 99%

Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

Schob

Hempel

Brožková

et al. 2021

Annals of Neurology

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Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lowerextremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantileonset form of HSP in a cohort of 8 patients with a uniform clinical presentation. Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. Results: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. Interpretation: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP.

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Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice

Cited by 15 publications

References 78 publications

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

The microtubule skeleton and the evolution of neuronal complexity in vertebrates

Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

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