An N‐terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice DOI Creative Commons
Sayaka Okuzono, Fumihiko Fujii, Daiki Setoyama

и другие.

Genes to Cells, Год журнала: 2024, Номер 29(9), С. 746 - 756

Опубликована: Июль 4, 2024

Abstract An autism‐associated gene Shank3 encodes multiple splicing isoforms, Shank3a‐f. We have recently reported that Shank3a/b‐knockout mice were more susceptible to kainic acid‐induced seizures than wild‐type at 4 weeks of age. Little is known, however, about how the N‐terminal and ankyrin repeat domains (NT‐Ank) Shank3a/b regulate molecular signals in developing brain. To explore functional roles Shank3a/b, we performed a mass spectrometry‐based proteomic search for proteins interacting with GFP‐tagged NT‐Ank. In this study, NT‐Ank was predicted form variety complexes total 348 proteins, which RNA‐binding ( n = 102), spliceosome 22), ribosome‐associated molecules 9) significantly enriched. Among them, an X‐linked intellectual disability‐associated protein, Nono, identified as NT‐Ank‐binding protein. Coimmunoprecipitation assays validated interaction Nono mouse agreement these data, thalamus aberrantly expressed isoforms genes, Nrxn1 Eif4G1 , before after acid treatment. These data indicate interacts postnatal brain, thereby regulating homeostatic expression genes birth.

Язык: Английский

RNA Polymerase II Activity Control of Gene Expression and Involvement in Disease DOI Creative Commons

James C. Kuldell,

Craig D. Kaplan

Journal of Molecular Biology, Год журнала: 2024, Номер 437(1), С. 168770 - 168770

Опубликована: Авг. 28, 2024

Gene expression is dependent on RNA Polymerase II (Pol II) activity in eukaryotes. In addition to determining the rate of synthesis for all protein coding genes, Pol serves as a platform recruitment factors and regulation co-transcriptional events, from processing chromatin modification remodeling. The transcriptome can be shaped by changes kinetics affecting itself or because alterations events that are responsive coupled with transcription. Genetic, biochemical, structural approaches model organisms have revealed critical insights into how works types regulate it. complexity generally increases organismal complexity. this review, we describe fundamental aspects shape gene expression, discuss recent advances elongation regulated altered function linked human disease aging.

Язык: Английский

Процитировано

4
ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation DOI Creative Commons
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman

и другие.

Molecular Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 23, 2024

Abstract Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical neurogenesis cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism somatic parallel Alzheimer’s disease progression. Furthermore, clinical trials with the fragment NAP (the investigational drug davunetide) showed efficacy women suffering from tauopathy progressive supranuclear palsy differentially boosted memory men (spatial) (verbal), exhibiting prodromal disease. While more prevalent boys women, both involve impaired neurogenesis. Here, we asked whether sex-dependently regulates Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, identified two-fold higher labeling hippocampal sub-ventricular zone ADNP-intact male versus female mice. Adnp haplo-insufficient ( +/− ) mice or CRSIPR/Cas9-edited present most neurodevelopmental syndrome mutation, p.Tyr718* (Tyr) dramatic reductions BrdU incorporation, resulting mutated females presenting than males. Treatment compensated reduction labeling. Mechanistically, RNAseq revealed male-specific Tyr down-regulation endoplasmic reticulum unfolded response genes sex-dependent organogenesis. Newly discovered mitochondrial accessibility was inhibited by Tyr718* mutation further revealing female-specific downregulation ATP6 . moderated much differential expression caused p.Tyr718*, accompanied neurotoxic, pro-inflammatory pro-apoptotic genes. Thus, key regulator that acts controlling canonical pathways, compensating fundamental deficiencies, striding toward development targeting related neurodevelopmental/neurodegenerative diseases.

Язык: Английский

Процитировано

3
Alternative Splicing in Autism Spectrum Disorder: Recent Insights from Mechanisms to Therapy DOI Creative Commons
Michael Zheng,

Nengcheng Bao,

Zhechao Wang

и другие.

Asian Journal of Psychiatry, Год журнала: 2025, Номер unknown, С. 104501 - 104501

Опубликована: Апрель 1, 2025

Alternative splicing (AS) is a vital and highly dynamic RNA regulatory mechanism that allows single gene to generate multiple mRNA protein isoforms. Dysregulation of AS has been identified as key contributor the pathogenesis autism spectrum disorders (ASD). A comprehensive understanding aberrant mechanisms their functional consequences in ASD can help uncover molecular basis disorder facilitate development therapeutic strategies. This review focuses on major events regulators associated with ASD, highlighting roles linking defective pathogenesis. In addition, discussion how emerging technologies, such long-read sequencing, single-cell spatial transcriptomics CRISPR-Cas systems are offering novel insights into role presented. Finally, splicing-based strategies evaluated, emphasizing potential address unmet clinical needs treatment.

Язык: Английский

Процитировано

0
Dysregulated RNA Binding Proteins and Alternative Splicing: Emerging Roles in Autism Spectrum Disorder DOI Open Access
Jiwon Jeong,

Hee Jeong Yoo,

Joon‐Yong An

и другие.

Molecules and Cells, Год журнала: 2025, Номер unknown, С. 100237 - 100237

Опубликована: Июнь 1, 2025

Dysregulation of gene expression can lead to abnormal brain function, with alternative splicing playing a crucial role in proper development. Emerging evidence suggests that dysregulated RNA-binding proteins (RBPs) contribute aberrant patterns, disrupting neuronal processes and increasing susceptibility neurodevelopmental disorders such as autism spectrum disorder (ASD). Understanding how misregulated RBPs alter mechanisms is for elucidating their ASD pathogenesis. Additionally, this knowledge essential developing targeted therapeutic strategies aimed at correcting splicing-related abnormalities. This review highlights recent advancements our understanding the interplay between explores promising RNAtargeting approaches.

Язык: Английский

Процитировано

0
An N‐terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice DOI Creative Commons
Sayaka Okuzono, Fumihiko Fujii, Daiki Setoyama

и другие.

Genes to Cells, Год журнала: 2024, Номер 29(9), С. 746 - 756

Опубликована: Июль 4, 2024

Abstract An autism‐associated gene Shank3 encodes multiple splicing isoforms, Shank3a‐f. We have recently reported that Shank3a/b‐knockout mice were more susceptible to kainic acid‐induced seizures than wild‐type at 4 weeks of age. Little is known, however, about how the N‐terminal and ankyrin repeat domains (NT‐Ank) Shank3a/b regulate molecular signals in developing brain. To explore functional roles Shank3a/b, we performed a mass spectrometry‐based proteomic search for proteins interacting with GFP‐tagged NT‐Ank. In this study, NT‐Ank was predicted form variety complexes total 348 proteins, which RNA‐binding ( n = 102), spliceosome 22), ribosome‐associated molecules 9) significantly enriched. Among them, an X‐linked intellectual disability‐associated protein, Nono, identified as NT‐Ank‐binding protein. Coimmunoprecipitation assays validated interaction Nono mouse agreement these data, thalamus aberrantly expressed isoforms genes, Nrxn1 Eif4G1 , before after acid treatment. These data indicate interacts postnatal brain, thereby regulating homeostatic expression genes birth.

Язык: Английский

Процитировано

1