AUTS2 isoforms control neuronal differentiation

Monderer-Rothkoff, Galya; Tal, Nitzan; Risman, Marina; Shani, Odem; Nissim-Rafinia, Malka; Malki-Feldman, Laura; Medvedeva, Vera; Groszer, Matthias; Meshorer, Eran; Shifman, Sagiv

doi:10.1038/s41380-019-0409-1

Cited by 42 publications

(64 citation statements)

References 53 publications

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“…The knockdown or pharmacological inhibition of P300 compromises the PRC1.5-mediated induction of a luciferase reporter [ 26 ], suggesting an important role for P300 in the transcriptional activity of this complex. The involvement of P300 with PRC1.5 and PRC1.3, which share the same complex composition, in activating gene transcription has been suggested in later studies ( Figure 3 b) [ 27 , 97 , 115 , 116 ]. Although Auts2 was not detected in the PRC1.3/5 isolated from mouse ES cells, which is likely due to its low expression in this cell type, Tex10 has been found to associate with PRC1.3/5 and may play a role in recruiting P300 [ 27 ].…”

Section: Prc1 In Transcription Regulationmentioning

confidence: 65%

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Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms

Geng

Gao

2020

IJMS

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Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. This review summarizes new advancements regarding the composition of mammalian PRC1 and accompanying explanations of how diverse PRC1-associated proteins participate in distinct transcription regulation mechanisms.

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Section: Prc1 In Transcription Regulationmentioning

confidence: 65%

“…Within PRC1.3/5, PCGF5 and presumably PCGF3 directly interact with AUTS2. AUTS2 makes direct contact with CK2 and P300, which are two factors that contribute to the transcriptional activation by PRC1.3/5 [ 26 , 27 , 97 ]. FBRS and FBRSL1 are homologs of AUTS2, but their roles in PRC1.3/5 remain unknown.…”

Section: Composition Of Prc1 Complexesmentioning

confidence: 99%

Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms

Geng

Gao

2020

IJMS

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“…One plausible hypothesis is that AUTS2 may have distinct roles for neural development in different cerebral cortical areas, which may depend on differences of AUTS2 isoforms expressed between neurons or on co-factors that differentially interact with each AUTS2 isoform. Monderer-Rothkoff et al have recently demonstrated that the long and short AUTS2 isoforms, each interacting with different co-factors, act opposingly on gene transcription in a cellular-context-dependent manner (Monderer-Rothkoff et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

AUTS2 Regulation of Synapses for Proper Synaptic Inputs and Social Communication

et al. 2020

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Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

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“…In addition to its transcription regulation functions, cytoplasmic AUTS2 also regulates actin cytoskeleton to control neuronal migration and neurite extension (Hori et al, 2014; Hori & Hoshino, 2017). It has been recently reported that AUTS2 controls neuronal differentiation, with a shift in expression from a long to a short isoform (Monderer‐Rothkoff et al, 2019). Moreover, alteration of AUTS2 has been considered as a “second‐hit” contributing to the variability of neurodevelopmental phenotypes in cases with other rare CNVs (Pizzo et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…One of these is a short isoform at the 3′ end, which includes the last 11 exons of the gene and is expressed in the human brain. The transcription start site of this short isoform is located in the middle of exon 9, and this alternative short mRNA uses the same reading frame as the conventional transcript (Beunders et al, 2013; Monderer‐Rothkoff et al, 2019). A relationship has been described between the loss of the terminal 3′ region of the AUTS2 gene and more severe manifestations of the disease, with the C‐terminus of AUTS2 being shown to be a major contributor to both neurodevelopmental and craniofacial phenotypes.…”

Section: Introductionmentioning

confidence: 99%

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects

Martı́nez-Delgado

López-Martín

Lara-Herguedas

et al. 2020

American J of Med Genetics Pt A

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Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C‐terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full‐length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

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AUTS2 isoforms control neuronal differentiation

Cited by 42 publications

References 53 publications

Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms

Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms

AUTS2 Regulation of Synapses for Proper Synaptic Inputs and Social Communication

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects

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