Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development

Huang, C.-W.; Lee, K.-Y.; Lin, P.-T.; Nian, Fang-Shin; Cheng, Haw-Yuan; Chang, C.-H.; Liao, C.-Y.; Su, Y.-L.; Seah, C.; Li, C.; Chen, Y.-F.; Lee, M.-H.; Tsai, J.-W.

doi:10.1111/nan.12890

Article (Scientific journals)

Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development

Huang, C.-W.; Lee, K.-Y.; Lin, P.-T. et al.

2023 • In Neuropathology and Applied Neurobiology, 49 (2)

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https://hdl.handle.net/2268/330648

DOI
10.1111/nan.12890

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36765387

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Keywords :

Add1; adducin; alternative splicing; dendritic spine; muscleblind-like; myotonic dystrophy; neural development; Animals; Brain; Dendritic Spines; Mice; Myotonic Dystrophy; Protein Isoforms; alpha adducin; alpha2 spectrin; complementary DNA; cre recombinase; messenger RNA; muscleblind like 2 protein; protein; RNA binding protein; spectrin; unclassified drug; isoprotein; adolescent; adult; adulthood; alternative RNA splicing; animal cell; animal experiment; animal model; animal tissue; Article; brain cell; brain development; brain slice; cell density; cell structure; confocal microscopy; controlled study; dynamics; electroporation; fetus; frameshift mutation; gene knockout; molecular interaction; molecular pathology; mouse; multiphoton microscopy; neural stem cell; newborn; newborn period; nonhuman; protein expression; protein phosphorylation; synapse; animal; brain; genetics; metabolism; pathology

Abstract :

[en] Aims: Muscleblind-like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models. Methods: To create Mbnl2 knockout neurons, cDNA encoding Cre-recombinase was delivered into neural progenitors of Mbnl2flox/flox mouse brains by in utero electroporation. The morphologies and dynamics of dendritic spines were monitored by confocal and two-photon microscopy in brain slices and live animals from the neonatal period into adulthood. To investigate the underlying molecular mechanism, we further detected the changes in the splicing and molecular interactions of proteins associated with spinogenesis. Results: We found that Mbnl2 knockout in cortical neurons decreased dendritic spine density and dynamics in adolescent mice. Mbnl2 ablation caused the adducin 1 (ADD1) isoform to switch from adult to fetal with a frameshift, and the truncated ADD1 failed to interact with alpha-II spectrin (SPTAN1), a critical protein for spinogenesis. In addition, expression of ADD1 adult isoform compensated for the reduced dendritic spine density in cortical neurons deprived of MBNL2. Conclusion: MBNL2 plays a critical role in maintaining the dynamics and homeostasis of dendritic spines in the developing brain. Mis-splicing of downstream ADD1 may account for the alterations and contribute to the DM brain pathogenesis. © 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Huang, C.-W.; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Lee, K.-Y.; Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan

Lin, P.-T.; Chang Gung University, College of Medicine, Taoyuan, Taiwan

Nian, Fang-Shin ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Cheng, Haw-Yuan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Faculty of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Chang, C.-H.; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

Liao, C.-Y.; Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

Su, Y.-L.

Seah, C.

Li, C.

More authors (3 more)

Language :

English

Title :

Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development

Publication date :

2023

Journal title :

Neuropathology and Applied Neurobiology

ISSN :

0305-1846

eISSN :

1365-2990

Publisher :

John Wiley and Sons Inc

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85153765420&doi=10.1111%2fnan.12890&partnerID=40&md5=b9770a04d7f12b6c07b8e8b87632974d

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