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Interneuron migration defects during corticogenesis contribute to Dyrk1a haploinsufficiency syndrome pathogenesis

Molecular Psychiatry (2025)Cite this article

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Abstract

Interneuron development is a crucial step of brain corticogenesis. When affected it often leads to brain dysfunctions like epilepsy, intellectual disabilities and autism spectrum disorder. Such defects are observed in the DYRK1A-haploinsufficiency syndrome, caused by mutations in DYRK1A, and commonly associated to cortical excitatory/inhibitory imbalance. However, how this imbalance is established in this syndrome remains elusive. Here, using mouse models and live imaging, we demonstrate that Dyrk1a specifically regulates the development of the cortical GABAergic system. We show that, unlike projection excitatory neurons, interneuron tangential migration relies on Dyrk1a dosage and kinase activity. We further reveal that Dyrk1a regulates actomyosin cytoskeleton remodeling during interneuron migration. Interestingly, mice with heterozygous inactivation of Dyrk1a in interneurons exhibited decreased interneuron density together with behavioral defects and epileptic activity, recapitulating phenotypes observed in human patients. Altogether, these data highlight the critical role of Dyrk1a in the development of the GABAergic system and the pathophysiology of DYRK1A-haploinsufficiency syndrome.

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Fig. 1: Dyrk1a haploinsufficiency affects interneuron distribution in the developing cortex.
Fig. 2: Dyrk1a dosage controls IN migration dynamics and morphology.
Fig. 3: Tangential migration relies on DYRK1A Kinase activity.
Fig. 4: Dyrk1a regulates actomyosin contractions during IN migration.
Fig. 5: Dyrk1a haploinsufficiency leads to abnormal localization of interneurons after birth.
Fig. 6: Dyrk1a haploinsufficiency leads to behavioral anomalies and epilepsy.

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Data availability

The data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus [91] and are accessible through GEO Series accession number GSE247752 for Dyrk1aDlxCre/+ and GSE247755 for Dyrk1a+/-.

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Acknowledgements

Gábor Szabó for providing the GAD65-EGFP mice. Laurent Meijer and Emmanuel Deau for providing LCTB-21 inhibitor and isoLCTB-21. Wojciech Krezel for providing the ASCL1 primary antibody. ICS animal facility, in particular Sophie Brignon and Milan Herrmann for their involvement in the project. All the staff of the IGBMC Platform of photonic microscopy, for their assistance in imaging experiments, and the IGBMC Genomeast platform, a member of the “France Génomique” consortium (ANR-10-INBS-0009), for the transcriptome studies. This work was funded by grants from the Fondation Jérôme-Lejeune (A.D and M-V.H, JLJ Postdoctoral fellowship and V.B for JLJ project N° 1647), the French state funds through the Agence Nationale de la Recherche under the project PRC DYRK-DOWN ANR-18-CE16-0020 (Y.H.; J.D.G), and support from the program Investissements d’Avenir labeled IdEx Unistra (ANR-10-IDEX-0002), a SFRI-STRAT’US project (ANR 20-SFRI-0012), EUR IMCBio (ANR-17-EURE-0023) to JDG and YH, INBS PHENOMIN (ANR-10-INBS-07 PHENOMIN) to YH, the ‘France Génomique’ consortium (ANR-10-INBS-0009) for the GenomeEast platform, and INSERM/CNRS and University of Strasbourg. P.T. and A.D. are, respectively, research assistants and research engineer at the University of Strasbourg. VN is an engineer assistant at the CNRS. VA is a PhD student at the ED414 Unistra. MdM and TLN were respectiveley a post-doct and PhD candidate at the CERBM GIE. VB and YH are respectively CNRS researcher and Principal investigator. J.D.G. is an INSERM investigator. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All the members of Y.H and J.G research groups for their feedback.

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  1. These authors contributed equally: Maria Victoria Hinckelmann, Aline Dubos.

Authors and Affiliations

  1. Université de Strasbourg, Centre National de la Recherche Scientifique (CNRS) UMR7104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Graffenstaden, F-67404, France

    Maria Victoria Hinckelmann, Aline Dubos, Victorine Artot, Gabrielle Rudolf, Thu Lan Nguyen, Peggy Tilly, Valérie Nalesso, Maria del Mar Muniz Moreno, Marie-Christine Birling, Juliette D. Godin, Véronique Brault & Yann Herault

  2. CELPHEDIA, PHENOMIN Institut Clinique de la Souris (ICS), Illkirch-Graffenstaden, F-67000, France

    Aline Dubos, Marie-Christine Birling & Yann Herault

Authors
  1. Maria Victoria Hinckelmann
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  2. Aline Dubos
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  3. Victorine Artot
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  4. Gabrielle Rudolf
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  5. Thu Lan Nguyen
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  6. Peggy Tilly
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  7. Valérie Nalesso
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  8. Maria del Mar Muniz Moreno
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  9. Marie-Christine Birling
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  10. Juliette D. Godin
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  11. Véronique Brault
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  12. Yann Herault
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Contributions

M-VH conceived and designed the experiments, performed and analyzed experiments, coordinated the study and wrote the manuscript. AD conceived and designed the experiments, performed and analyzed experiments. VA performed and analyzed time-lapse experiments with LCTB-21 treatment, and designed cartoons. GR performed and analyzed EEG studies. T-LN performed the kinase activity assay. PT performed in utero electroporations. MdeM performed bulk RNA-Seq analyses and VN further analyzed this data. M-CB developed and validated the Dyrk1aK188R/+ mouse model. JDG conceived and supervised in utero electroporation experiments. VB conceived, performed and analyzed behavioral studies and provided financial support. YH conceived, coordinated and supervised the study, and provided the financial support.

Corresponding author

Correspondence to Yann Herault.

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Hinckelmann, M.V., Dubos, A., Artot, V. et al. Interneuron migration defects during corticogenesis contribute to Dyrk1a haploinsufficiency syndrome pathogenesis. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03109-7

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  • DOI: https://doi.org/10.1038/s41380-025-03109-7

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