Epigenetic Regulation of Mode of cortical Interneuron Migration

• Applicant: Professorin Dr. Geraldine Zimmer-Bensch
• Subject Area: Developmental Neurobiology ; General Genetics and Functional Genome Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464321698

Understanding the cellular and molecular mechanisms that govern the timely ordered developmental processes during brain unfolding like neuronal differentiation and migration, is a fundamental goal in neuroscience. The different steps of neuronal maturation rely on stage-specific gene expression programs, which are modulated by local environmental stimuli. This becomes clearly evident for the migration of inhibitory GABAergic cortical interneurons from their sites of origin within the basal telencephalon to their final cortical target regions. After tangentially spreading over the different cortical areas, interneurons switch to a radial mode of migration to invade the cortical layers. These different steps are modulated by secreted or membrane-bound proteins, which trigger stage-specific gene expression programs that direct the physiological responses such as cytoskeletal remodeling. To decipher the interplay of environmental signals and transcriptional programs underlying this switch in migration mode is critical, as its timing defines the final interneuron number in a given cortical area. Understanding these processes and signaling networks is prerequisite to approach the etiology of neuropsychiatric diseases like schizophrenia and epilepsy, as such disorders at least in part rely on defective development and distribution of inhibitory GABAergic interneurons. Epigenetic gene regulatory mechanisms, such as DNA methylation, histone modification and non-coding RNAs, seem to play a key role in integrating stimuli from the local microenvironment into the genome, thereby influencing stage-specific transcriptional networks. However, so far little is known about discrete epigenetic profiles in setting up stage-specific transcriptional programs in cortical interneurons, and how they can be shaped by external signals.In preliminary studies we provided evidence that the DNA methyltransferase 1 (DNMT1) regulates stage-specific gene expression in migrating cortical interneurons. Further, we found that DNMT1 binding to specific gene loci and to particular lncRNAs can be altered upon external stimulation with an important regulatory membrane protein. This fits to the proposed function of lncRNAs in targeting DNA methylation. Based on these data, we here will address the role of stage-specific DNMT1-dependent DNA methylation for instructing transcriptional networks that direct the tangential to radial switch of cortical interneuron migration. We further ask, whether DNMT1 targeting depends on changing microenvironment and lncRNA function. To this end, we will apply a battery of innovative methods including mouse genetics, high-throughput sequencing of cortical interneurons, and sophisticated in vivo and in vitro functional validation approaches. Besides contributing to the understanding of neuropsychiatric disease etiology, this project will set the basis to develop epigenetic-based therapy strategies on the long run.

• DFG Programme: Research Grants