The role of the DNA Methyltransferase1 (DNMT1) in the development of somatostatin (SST)-positive cortical interneurons

• Applicant: Professorin Dr. Geraldine Zimmer-Bensch
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427999744

• Final Report Year: 2024

Final Report Abstract

GABAergic interneurons are crucial for cortical information processing, and disruptions in their development are linked to conditions like autism, epilepsy, and schizophrenia. DNMT1-mediated DNA methylation plays a vital role in cortical interneuron development. Building on our previous work on DNMT1's impact on interneuron migration, we investigated its role in the development of SOM-positive interneurons, focusing on subtype-specific programs. Phenotypic analysis of mice with DNMT1 deletion revealed altered SOM-interneuron density in different cortical layers, influencing layer thicknesses and contributing to behavioral abnormalities. Embryonic analyses showed disrupted migration patterns, with interneurons prematurely exiting migratory streams in the developing cortex and impacting cortical progenitors. High-throughput sequencing revealed altered gene expression related to interneuron development, migration, adhesion, and membrane vesicle formation in E14.5 interneurons upon Dnmt1 deletion. Dnmt1 deletion increased e.g. Ncam1 expression, crucial for proper migration. In a cell model we showed that DNMT1-mediated DNA methylation mediated through lncRNA-dependent recruitment modulates Ncam1 expression. In summary, our findings underscore the critical role of DNMT1 in ensuring proper SOM-interneuron migration, influencing cortical progenitors and the generation of deep and upper layer neurons, thereby ensuring proper cortical functionality.

Publications

• Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution. Cells, 8(11), 1399.
  Zimmer-Bensch, Geraldine
  
• DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes. International Journal of Molecular Sciences, 21(15), 5420.
  Bayer, Cathrin; Pitschelatow, Georg; Hannemann, Nina; Linde, Jenice; Reichard, Julia; Pensold, Daniel & Zimmer-Bensch, Geraldine
  
• DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons. Frontiers in Cell and Developmental Biology, 8.
  Hahn, Anne; Pensold, Daniel; Bayer, Cathrin; Tittelmeier, Jessica; González-Bermúdez, Lourdes; Marx-Blümel, Lisa; Linde, Jenice; Groß, Jonas; Salinas-Riester, Gabriela; Lingner, Thomas; von Maltzahn, Julia; Spehr, Marc; Pieler, Tomas; Urbach, Anja & Zimmer-Bensch, Geraldine
  
• Neuronal Lhx1 expression is regulated by DNMT1-dependent modulation of histone marks. Epigenetics, 15(11), 1259-1274.
  Symmank, Judit; Bayer, Cathrin; Reichard, Julia; Pensold, Daniel & Zimmer-Bensch, Geraldine
  
• EphrinA5 regulates cell motility by modulating Snhg15/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter. Epigenetics & Chromatin, 16(1).
  Yildiz, Can Bora; Kundu, Tathagata; Gehrmann, Julia; Koesling, Jannis; Ravaei, Amin; Wolff, Philip; Kraft, Florian; Maié, Tiago; Jakovcevski, Mira; Pensold, Daniel; Zimmermann, Olav; Rossetti, Giulia; Costa, Ivan G. & Zimmer-Bensch, Geraldine