AUTS2 isoforms control neuronal differentiation.

Animals Cell Differentiation Cytoskeletal Proteins Exons Mice Neurons / cytology Phenotype Protein Isoforms / genetics Transcription Factors / genetics

Journal

Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835

Informations de publication

Date de publication:
02 2021
Historique:
received: 27 11 2015
accepted: 18 03 2019
revised: 15 03 2019
pubmed: 7 4 2019
medline: 15 5 2021
entrez: 7 4 2019
Statut: ppublish

Résumé

Mutations in AUTS2 are associated with autism, intellectual disability, and microcephaly. AUTS2 is expressed in the brain and interacts with polycomb proteins, yet it is still unclear how mutations in AUTS2 lead to neurodevelopmental phenotypes. Here we report that when neuronal differentiation is initiated, there is a shift in expression from a long isoform to a short AUTS2 isoform. Yeast two-hybrid screen identified the splicing factor SF3B1 as an interactor of both isoforms, whereas the polycomb group proteins, PCGF3 and PCGF5, were found to interact exclusively with the long AUTS2 isoform. Reporter assays showed that the first exons of the long AUTS2 isoform function as a transcription repressor, but the part that consist of the short isoform acts as a transcriptional activator, both influenced by the cellular context. The expression levels of PCGF3 influenced the ability of the long AUTS2 isoform to activate or repress transcription. Mouse embryonic stem cells (mESCs) with heterozygote mutations in Auts2 had an increase in cell death during in vitro corticogenesis, which was significantly rescued by overexpressing the human AUTS2 transcripts. mESCs with a truncated AUTS2 protein (missing exons 12-20) showed premature neuronal differentiation, whereas cells overexpressing AUTS2, especially the long transcript, showed increase in expression of pluripotency markers and delayed differentiation. Taken together, our data suggest that the precise expression of AUTS2 isoforms is essential for regulating transcription and the timing of neuronal differentiation.

Identifiants

DOI: 10.1038/s41380-019-0409-1 PMID: 30953002
pubmed: 30953002
doi: 10.1038/s41380-019-0409-1
pii: 10.1038/s41380-019-0409-1
doi:

Substances chimiques

Auts2 protein, mouse 0
Cytoskeletal Proteins 0
Protein Isoforms 0
Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

666-681

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Auteurs

Galya Monderer-Rothkoff (G)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Nitzan Tal (N)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Marina Risman (M)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Odem Shani (O)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Malka Nissim-Rafinia (M)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Laura Malki-Feldman (L)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Vera Medvedeva (V)

Inserm, UMR-S839, Sorbonne Universités, Pierre et Marie Curie Université Paris 06, Institut du Fer à Moulin, Paris, 75005, France.

Matthias Groszer (M)

Inserm, UMR-S839, Sorbonne Universités, Pierre et Marie Curie Université Paris 06, Institut du Fer à Moulin, Paris, 75005, France.

Eran Meshorer (E)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Sagiv Shifman (S)

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. sagiv.shifman@mail.huji.ac.il.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cytosquelette › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Exons › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Cellules › Neurones › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Phénomènes génétiques › Phénotype › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › AUTS2 isoforms control neuronal differentiation.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › AUTS2 isoforms control neuronal differentiation.