Mouse Models of Mutations and Variations in Autism Spectrum Disorder-Associated Genes: Mice Expressing Caps2/Cadps2 Copy Number and Alternative Splicing Variants

Sadakata, Tetsushi; Shinoda, Yo; Sato, Akira; Iguchi, Hirotoshi; Ishii, Chiaki; Matsuo, Makoto; Yamaga, Ryosuke; Furuichi, Teiichi

doi:10.3390/ijerph10126335

Cited by 12 publications

(6 citation statements)

References 70 publications

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“…Additionally, subtype IB cells had the highest expression of Ca 2+ -dependent activator protein for secretion 2 (Cadps2; Figure 5A), which is involved in cell survival and the activitydependent release of the brain-derived neurotrophic factor (BDNF; Sadakata et al, 2004;Shinoda et al, 2011). BDNF is involved in neuronal maturation and synaptic plasticity (Sadakata et al, 2007(Sadakata et al, , 2013. Intriguingly, Bdnf, and Ntf3 expression, as well as their receptor Ntrk2, are high in type IB, although present in the other subtypes ( Figure 5A, Supplementary Figure S7).…”

Section: Sgni Subtypes Have Distinct Physiological and Signaling Propmentioning

confidence: 99%

Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea

Grandi

Tomasi

Mustapha

2020

Front. Mol. Neurosci.

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In the mature cochlea, each inner hair cell (IHC) is innervated by multiple spiral ganglion neurons of type I (SGNI). SGNIs are morphologically and electro-physiologically diverse. Also, they differ in their susceptibility to noise insult. However, the molecular underpinnings of their identity and physiological differences remain poorly understood. In this study, we developed a novel triple transgenic mouse, which enabled the isolation of pure populations of SGNIs and the analysis of a 96-gene panel via single-cell qPCR. We found three distinct populations of Type I SGNs, which were marked by their exclusive expression of Lmx1a, Slc4a4, or Mfap4/Fzd2, respectively, at postnatal days P3, P8, and P12. Our data suggest that afferent SGN subtypes are established genetically before the onset of hearing and that the expression of key physiological markers, such as ion channels, is heterogeneous and may be underlying the heterogeneous firing proprieties of SGNIs.

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Section: Sgni Subtypes Have Distinct Physiological and Signaling Propmentioning

confidence: 99%

Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea

Grandi

Tomasi

Mustapha

2020

Front. Mol. Neurosci.

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“…including CADPS2 have been associated with disorders affecting cognitive functions and susceptibility to autism (Okamoto et al, 2011, Sadakata et al, 2013. Finally Lim domain binding (LDB) protein 2 has been suggested to be important for the regulation of cell fate differentiation (Leone et al, 2017) and to play a role in vascular remodelling (Choi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and genetic analyses reveal potential causal drivers for intractable partial epilepsy

Guelfi

Botía

Thom

et al. 2019

Brain

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Mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE+HS) represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. mTLE is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by SNPs in regulatory elements (eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies (GWAS). We have performed a whole (gene and exon-level) transcriptome analysis on cortical tissue samples (Brodmann areas 20 and 21) from 86 patients with mTLE+HS and 75 neurologically healthy controls. Genome-wide genotyping data from the same individuals (patients and controls) were analysed and paired with the transcriptome data. We report potential epilepsy-risk eQTLs, some of which are specific to tissue from patients with mTLE+HS. We also found large transcriptional and splicing deregulation in mTLE+HS tissue as well as gene networks involving neuronal and glial mechanisms that provide new insights into the cause and maintenance of the seizures. These data (available via the "Seizubraineac" web-tool resource, www.seizubraineac.org) will facilitate the identification of new therapeutic targets and biomarkers as well as genetic risk variants that could influence epilepsy and pharmacoresistance.

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“…Moreover, CADPS2 plays an important function on the synaptic circuits throughout the activity-dependent release of neurotrophic factor (BDNF). Indeed, genetic variants in CADPS2 gene were associated to ASD and CADPS2 KO mice have shown impairments in behavioral phenotypes [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Gene-based analysis of ADHD using PASCAL: a biological insight into the novel associated genes

et al. 2019

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Background: Attention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder (NDD) which may significantly impact on the affected individual's life. ADHD is acknowledged to have a high heritability component (70-80%). Recently, a meta-analysis of GWAS (Genome Wide Association Studies) has demonstrated the association of several independent loci. Our main aim here, is to apply PASCAL (pathway scoring algorithm), a new gene-based analysis (GBA) method, to the summary statistics obtained in this meta-analysis. PASCAL will take into account the linkage disequilibrium (LD) across genomic regions in a different way than the most commonly employed GBA methods (MAGMA or VEGAS (Versatile Gene-based Association Study)). In addition to PASCAL analysis a gene network and an enrichment analysis for KEGG and GO terms were carried out. Moreover, GENE2FUNC tool was employed to create gene expression heatmaps and to carry out a (DEG) (Differentially Expressed Gene) analysis using GTEX v7 and BrainSpan data. Results: PASCAL results have revealed the association of new loci with ADHD and it has also highlighted other genes previously reported by MAGMA analysis. PASCAL was able to discover new associations at a gene level for ADHD: FEZF1 (p-value: 2.2 × 10 − 7 ) and FEZF1-AS1 (p-value: 4.58 × 10 − 7 ). In addition, PASCAL has been able to highlight association of other genes that share the same LD block with some previously reported ADHD susceptibility genes. Gene network analysis has revealed several interactors with the associated ADHD genes and different GO and KEGG terms have been associated. In addition, GENE2FUNC has demonstrated the existence of several up and down regulated expression clusters when the associated genes and their interactors were considered. Conclusions: PASCAL has been revealed as an efficient tool to extract additional information from previous GWAS using their summary statistics. This study has identified novel ADHD associated genes that were not previously reported when other GBA methods were employed. Moreover, a biological insight into the biological function of the ADHD associated genes across brain regions and neurodevelopmental stages is provided.

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Mouse Models of Mutations and Variations in Autism Spectrum Disorder-Associated Genes: Mice Expressing Caps2/Cadps2 Copy Number and Alternative Splicing Variants

Cited by 12 publications

References 70 publications

Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea

Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea

Transcriptomic and genetic analyses reveal potential causal drivers for intractable partial epilepsy

Gene-based analysis of ADHD using PASCAL: a biological insight into the novel associated genes

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