Dormant state of quiescent neural stem cells links Shank3 mutation to autism development

Kim, Hongwon; Cho, Byounggook; Park, Hanseul; Kim, Junyeop; Kim, Siyoung; Shin, Jaein; Lengner, Christopher J.; Won, Kyoung Jae; Kim, Jong-Pil

doi:10.1038/s41380-022-01563-1

Cited by 13 publications

(19 citation statements)

References 46 publications

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“…9 ) [ 70 ], providing molecular insights into the management of gene expression by SHANK3. By employing CRISPR/Cas9 nuclease systems to generate SHANK3-deficient iPSCs, an increase in qNSCs and a decrease in aNSCs were observed, which is consistent with the findings of previous murine studies [ 49 ]. PMDS-iPSCs can differentiate into slightly fewer neurons, and their excitatory synaptic transmission is impaired, as measured by the expression of GluA1 and GluN1 proteins and the number of Synapsin1 + and Homer1 + /Synapsin1 + [ 71 ].…”

Section: Shank and Stem Cellssupporting

confidence: 91%

“…LAMP1 + lysosomes exhibit abnormal “clustered” distribution, fusion, and autolysosome formation, accompanied by the activation of inflammatory factors NLRP3 and Caspase1 [ 10 ]. Recently, research has authenticated that SHANK3 deficiency decreases the number of total NSCs, active NSCs (aNSCs), and neuroblasts in SVZ and SGZ [ 49 ]. In contrast, quiescent NSCs (qNSCs) increased are associated with social deficits due to abnormal epigenetic characteristics, such as histone H3 lysine 4 (H3K4) trimethylation accumulation caused by an increase in KMT2A levels (Fig.…”

Section: Shank and Stem Cellsmentioning

confidence: 99%

“…In contrast, quiescent NSCs (qNSCs) increased are associated with social deficits due to abnormal epigenetic characteristics, such as histone H3 lysine 4 (H3K4) trimethylation accumulation caused by an increase in KMT2A levels (Fig. 8 ) [ 49 ]. The study further demonstrates that the inhibition of KMT2A and H3K4me3, including molecular and pharmacological inhibition in qNSCs, can restore adult neurogenesis and ameliorate social deficits [ 49 ].…”

Section: Shank and Stem Cellsmentioning

confidence: 99%

“…8 ) [ 49 ]. The study further demonstrates that the inhibition of KMT2A and H3K4me3, including molecular and pharmacological inhibition in qNSCs, can restore adult neurogenesis and ameliorate social deficits [ 49 ]. These findings offer a novel therapeutic strategy to control qNSC activity as a potential therapeutic target for autism.…”

Section: Shank and Stem Cellsmentioning

confidence: 99%

“…SHANK family proteins directly or indirectly govern the expression of a remarkably large number of genes (Table 1), indicating their significant role in gene regulation. SHANK3 can typically bind to β-catenin; when the absence of SHANK3 results in the translocation of β-catenin from synapses into the nucleus, where it can form complexes with transcription factor TCF/LEF to activate target genes such as histone deacetylase (HDAC) 2, euchromatic histone-lysine N-methyltransferase (EHMT) 1/2, and histone-lysine methyltransferase 2 A (KMT2A), thereby impacting synaptic function and stem cell behavior [47][48][49]. Furthermore, earlier studies have exposed that SHANK forms a complex with Rho guanine nucleotide exchange factor 7 (β-PIX) [50] that regulates Rac1/PAK/Confilin activity to modulate cortical actin filaments and influences NMDAR synaptic function [51].…”

Section: Regulation Of Signaling Pathways By the Shank Familymentioning

confidence: 99%

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SHANK family on stem cell fate and development

et al. 2022

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SH3 and multiple ankyrin repeat domains protein (SHANK) 1, SHANK2, and SHANK3 encode a family of postsynaptic scaffolding proteins present at glutamatergic synapses and play a crucial role in synaptogenesis. In the past years, studies have provided a preliminary appreciation and understanding of the influence of the SHANK family in controlling stem cell fate. Here, we review the modulation of SHANK gene expression and their related signaling pathways, allowing for an in-depth understanding of the role of SHANK in stem cells. Besides, their role in governing stem cell self-renewal, proliferation, differentiation, apoptosis, and metabolism are explored in neural stem cells (NSCs), stem cells from apical papilla (SCAPs), and induced pluripotent stem cells (iPSCs). Moreover, iPSCs and embryonic stem cells (ESCs) have been utilized as model systems for analyzing their functions in terms of neuronal development. SHANK-mediated stem cell fate determination is an intricate and multifactorial process. This study aims to achieve a better understanding of the role of SHANK in these processes and their clinical applications, thereby advancing the field of stem cell therapy.

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Section: Shank and Stem Cellssupporting

confidence: 91%

Section: Shank and Stem Cellsmentioning

confidence: 99%

Section: Shank and Stem Cellsmentioning

confidence: 99%

Section: Shank and Stem Cellsmentioning

confidence: 99%

Section: Regulation Of Signaling Pathways By the Shank Familymentioning

confidence: 99%

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SHANK family on stem cell fate and development

et al. 2022

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Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance

Fard,

Sadeghi,

Pajoohesh

et al. 2024

American J of Med Genetics Pt B

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Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation‐linked H3K4me2/3, H3K9ac, and H3K27ac, and repression‐linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

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