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Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity

Author

Listed:
  • Raphaël Dos Reis

    (INM, Université Montpellier, CNRS, INSERM)

  • Etienne Kornobis

    (C2RT, Institut Pasteur
    Hub Bioinformatique et Biostatistique, Département de Biologie Computationnelle – USR 3756 CNRS, Institut Pasteur)

  • Alyssa Pereira

    (INM, Université Montpellier, CNRS, INSERM)

  • Frederic Tores

    (BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine)

  • Judit Carrasco

    (UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur
    Max Planck Institute of Immunobiology and epigenetics)

  • Candice Gautier

    (Institut Imagine, INSERM - U1163, Unité mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques)

  • Céline Jahannault-Talignani

    (INM, Université Montpellier, CNRS, INSERM)

  • Patrick Nitschké

    (BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine)

  • Christian Muchardt

    (UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur)

  • Andreas Schlosser

    (University of Würzburg)

  • Hans Michael Maric

    (University of Würzburg, Biotechnology and Biophysics, Rudolf Virchow Zentrum Gebäude D15)

  • Fabrice Ango

    (INM, Université Montpellier, CNRS, INSERM)

  • Eric Allemand

    (UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur
    Institut Imagine, INSERM - U1163, Unité mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques)

Abstract

Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and gamma-aminobutyric acid A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.

Suggested Citation

  • Raphaël Dos Reis & Etienne Kornobis & Alyssa Pereira & Frederic Tores & Judit Carrasco & Candice Gautier & Céline Jahannault-Talignani & Patrick Nitschké & Christian Muchardt & Andreas Schlosser & Han, 2022. "Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31264-w
    DOI: 10.1038/s41467-022-31264-w
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    1. Donny D. Licatalosi & Aldo Mele & John J. Fak & Jernej Ule & Melis Kayikci & Sung Wook Chi & Tyson A. Clark & Anthony C. Schweitzer & John E. Blume & Xuning Wang & Jennifer C. Darnell & Robert B. Darn, 2008. "HITS-CLIP yields genome-wide insights into brain alternative RNA processing," Nature, Nature, vol. 456(7221), pages 464-469, November.
    2. Thomas A. Ray & Kelly Cochran & Chris Kozlowski & Jingjing Wang & Graham Alexander & Martha A. Cady & William J. Spencer & Philip A. Ruzycki & Brian S. Clark & Annelies Laeremans & Ming-Xiao He & Xiao, 2020. "Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    3. Hans Michael Maric & Vikram Babu Kasaragod & Torben Johann Hausrat & Matthias Kneussel & Verena Tretter & Kristian Strømgaard & Hermann Schindelin, 2014. "Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
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