Neuron-enriched phosphatase and actin regulator 3 (Phactr3)/ nuclear scaffold-associated PP1-inhibiting protein (Scapinin) regulates dendritic morphology via its protein phosphatase 1-binding domain

Miyata, Tomoaki; Kikuchi, Keietsu; Ihara, Daisuke; Kaito, Maki; Ishibashi, Yuta; Hakamata, Tomoyuki; Yamada, Tetsuya; Ishikawa, Mitsuru; Mizukoshi, Miho; Shoji, Shizuku; Tsuda, Masashi; Hida, Yamato; Ohtsuka, Toshihisa; Kaneda, Marisa; Tabuchi, Akiko

doi:10.1016/j.bbrc.2020.05.006

Cited by 7 publications

(6 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, some of the OTUD7A LoF downregulated genes are strong candidates that may mediate the "causal" effect of OTUD7A LoF. For instance, the second most downregulated gene (log2_FC = -0.78, p = 7.3 × 10 -5 ), phosphatase and actin regulator 3 S2), encodes a neuron-enriched protein that regulates dendritic morphology (Miyata et al, 2020). Another plausible mediator and the third most downregulated gene (log2_FC = -0.64, p = 8.5 × 10 -5 ), Ras guanine nucleotide releasing factor 1 (RASGRF1) (Figure 6B, Table S2), serves as an NMDAR-dependent regulator of the ERK kinase pathway, facilitating neurotrophin-induced neurite outgrowth (Krapivinsky et al, 2003;Talebian et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Kozlova

Zhang

Kotlar

et al. 2022

The American Journal of Human Genetics

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Kozlova

Zhang

Kotlar

et al. 2022

The American Journal of Human Genetics

View full text Add to dashboard Cite

“…Second, some of the OTUD7A LoF downregulated genes are strong candidates that may mediate the “causal” effect of OTUD7A LoF. For instance, the second most downregulated gene (log2_FC = -0.78, p = 7.3 × 10 -5 ), phosphatase and actin regulator 3 ( PHACTR3 ) (Figure 6B, Table S2), encodes a neuron-enriched protein that regulates dendritic morphology (Miyata et al, 2020). Another plausible mediator and the third most downregulated gene (log2_FC = -0.64, p = 8.5 × 10 -5 ), Ras guanine nucleotide releasing factor 1 ( RASGRF1 ) (Figure 6B, Table S2), serves as an NMDAR-dependent regulator of the ERK kinase pathway, facilitating neurotrophin-induced neurite outgrowth (Krapivinsky et al, 2003; Talebian et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function of OTUD7A in the schizophrenia-associated 15q13.3 deletion impairs synapse development and function in human neurons

Kozlova

Zhang

Kotlar

et al. 2022

Preprint

View full text Add to dashboard Cite

Identifying causative gene(s) within disease-associated large genomic regions of copy number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases, but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR/Cas9 engineering. The mutant iNs showed a ~50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

show abstract

“…5d). Notably, Slit3 encodes a repulsive axon guidance molecule 23,24 , and Phactr3 has been shown to be involved in regulating axonal morphology 25,26 . To understand how the differentially expressed genes in CBX-projecting neurons are regulated, we explored DMRs that were hypo-methylated in CBX-projecting neurons.…”

Section: Epi-retro-seq and Neurotransmitter Usage In Hindbrain Projec...mentioning

confidence: 99%

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Zhou

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

Single-cell genetic and epigenetic analyses parse the brain′s billions of neurons into thousands of ″cell type″ clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source→target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

show abstract

Neuron-enriched phosphatase and actin regulator 3 (Phactr3)/ nuclear scaffold-associated PP1-inhibiting protein (Scapinin) regulates dendritic morphology via its protein phosphatase 1-binding domain

Cited by 7 publications

References 26 publications

Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Loss-of-function of OTUD7A in the schizophrenia-associated 15q13.3 deletion impairs synapse development and function in human neurons

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Contact Info

Product

Resources

About