Positive regulation of neocortical synapse formation by the Plexin-D1 receptor

Wang, F.; Eagleson, Kathie L.; Levitt, Pat

doi:10.1016/j.brainres.2015.05.005

Cited by 10 publications

(14 citation statements)

References 41 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One day post-treatment, there was already a significant increase in dendritic length (t 12 = −6.15, p<0.001, Figure 3D) and number of branch points (t 12 = −4.67, p<0.001, Figure 3E) in neurons treated with HGF (length: 1296.60µm [95% CI: 1288.67, 1364.53], branch points: 12.02 [95% CI: 10.24, 13.80]) compared to untreated controls (length: 965.56µm [95% CI: 884.87, 1046.25], branch points: 7.14 [95% CI: 6.13, 8.15]), consistent with a previous report in vitro (Finsterwald and Martin, 2011). Synaptic density also was measured in a subfield of the GFP-labeled proximal dendritic tree using a customized plug-in developed in our laboratory (Wang et al, 2015). Within 24 hr of HGF addition, there was a significant increase in synaptic density (t 12 = −2.74, p=0.012, Figure 3G), defined by co-localization of synapsin-1 and PSD-95 (Figure 3F), following HGF stimulation (untreated: 2.81/100µm 2 [95% CI: 2.20, 3.42], HGF: 4.54/100µm 2 [95% CI: 3.47, 5.61]).…”

Section: Resultsmentioning

confidence: 99%

“…In a pilot study, using data generated in a previous publication (Wang et al, 2015), we determined that 8 – 10 neurons was sufficient to reflect stably the average synapse density per coverslip (Supplementary Figure 1), with no differences when analyzing additional neurons/coverslip. Cell sampling was done by making non-overlapping, vertical sweeps of the coverslip in the GFP channel.…”

Section: Methodsmentioning

confidence: 99%

“…Quantification of cumulative mean synapse density with increasing number of cells analyzed across 10 different coverslips using data generated in a previous publication (Wang et al, 2015). Each coverslip is represented by a different colored symbol.…”

Section: Supplementary Materialsmentioning

confidence: 99%

See 2 more Smart Citations

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Eagleson

Lane

McFadyen‐Ketchum

et al. 2016

Developmental Neurobiology

View full text Add to dashboard Cite

Hepatocyte growth factor (HGF) activation of the MET receptor tyrosine kinase influences multiple neurodevelopmental processes. Evidence from human imaging and mouse models shows that, in the forebrain, disruptions in MET signaling alter circuit formation and function. One likely means of modulation is by controlling neuron maturation. Here, we examined the signaling mechanisms through which MET exerts developmental effects in the neocortex. In situ hybridization revealed that hgf is located near MET-expressing neurons, including deep neocortical layers and periventricular zones. Western blot analyses of neocortical crude membranes demonstrated that HGF-induced MET autophosphorylation peaks during synaptogenesis, with a striking reduction in activation between P14 and P17 just prior to pruning. In vitro analysis of postnatal neocortical neurons assessed the roles of intracellular signaling following MET activation. There is rapid, HGF-induced phosphorylation of MET, ERK1/2 and Akt that is accompanied by two major morphological changes increases in total dendritic growth and synapse density. Selective inhibition of each signaling pathway altered only one of the two distinct events. MAPK/ERK pathway inhibition significantly reduced the HGF-induced increase in dendritic length, but had no effect on synapse density. In contrast, inhibition of the PI-3K/Akt pathway reduced HGF-induced increases in synapse density, with no effect on dendritic length. The data reveal a key role for MET activation during the period of neocortical neuron growth and synaptogenesis, with distinct biological outcomes mediated via discrete MET-linked intracellular signaling pathways in the same neurons.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Eagleson

Lane

McFadyen‐Ketchum

et al. 2016

Developmental Neurobiology

View full text Add to dashboard Cite

show abstract

“…Of the remaining genes, there were several with a plausible role in the biology of SMI, but not thus far implicated in any disease phenotype. These genes, with the ontology descriptions and plausible biological implications, are provided in Table (c) …”

Section: Resultsmentioning

confidence: 99%

“…These genes, with the ontology descriptions and plausible biological implications, are provided in Table 2(c). [53][54][55][56][57][58] Enrichment of coding variants with plausible functional role in SMI The NSD-B set consisted of 248 variants; of these, except for rs570064523 in the PCSK1 gene, which was identified in cases from two families (G and H), no other overlap at the level of family was noted for the remaining 247 variants (Appendix S2, Table S3). In the 'protein domains' category tested using the Interpro database as the source, the term 'epidermal growth factor like domain' showed a nominally significant enrichment with P = 0.0013, Benjamini-Hochberg false discovery rate corrected P = 0.073.…”

Section: Sample Characteristicsmentioning

confidence: 99%

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Ganesh

Pallikonda

Nadella

et al. 2018

Psychiatry Clin Neurosci

View full text Add to dashboard Cite

Aim Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome‐wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next‐generation sequencing may add to the understanding of the genetic architecture of SMI. Methods We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. Results We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. Conclusion Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

show abstract

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Dias

Estruch

Graham

et al. 2016

The American Journal of Human Genetics

139

174

View full text Add to dashboard Cite

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.

show abstract

Positive regulation of neocortical synapse formation by the Plexin-D1 receptor

Cited by 10 publications

References 41 publications

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Distinct intracellular signaling mediates C‐MET regulation of dendritic growth and synaptogenesis

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Contact Info

Product

Resources

About