The role of DNA-Methyltransferase1 in cortical GABAergic interneuron differentiation, development and function

• Applicant: Professorin Dr. Geraldine Zimmer-Bensch, since 6/2014
• Subject Area: Developmental Neurobiology
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221259022

Shaping excitatory responses of pyramidal neurons by the very diverse group of GABAergic interneurons falling into 20 highly diverse subpopulations is crucial for cortical circuits, plasticity and higher cognitive functions. Abnormalities in interneuron number, composition and function have been implicated in a wide range of neurological disorders. Thus, deciphering the developmental determinants that sculpt their physiological diversity seems critical in any attempt to understand the logic behind their integration into cortical circuits, as well as causes for cortical dysfunction. A paucity of specific interneuron subtype markers further complicates investigations on the molecular mechanisms underlying the generation of cortical interneuron heterogeneity. It has become clear that different classes of cortical interneurons are generated in a temporally regulated fashion within distinct domains of the basal telencephalon, from where they migrate over long distances along predefined routes to the cortex. This temporal and spatial origin of cortical interneurons seems predictive for their intrinsic properties in respect to their mature function. Codes of transcription factors and specific signaling molecules were identified to regulate interneuron subtype generation and migration. Moreover, epigenetic mechanisms, like DNA methylation in particular, also govern cell fate decisions. We have found that DNA-methyltransferase 1 (DNMT1) is specifically expressed in a particular interneuron subtype generating domain, the preoptic area (POA), where neuropeptideY expressing interneurons destined for the upper cortical layers are generated. In contrast, DNMT1ýexpression was absent in other interneuron generating domains. In previous studies we have shown that POAýderived interneurons migrate stereotypically along a particular route through the basal telencephalon, navigated by cell-type specific expression of guidance receptors. Furthermore, inhibiting DNMT1 function by application of shRNA disturbs the proper migration of POAýderived interneurons, indicating changes in the receptor repertoire typical for these cells. Thus, the ultimate goal of this proposal is to determine the role of DNA methylation in interneuron subtype specification, development and function. For this purpose, conditional DNMT1 knockout mice will be analysed using descriptive, functional and behavioral approaches. Transcriptome analysis of individual embryonic cortical interneuron subtypes and methylation profiling will help to identify targets of DNMT1 in interneuron development. Furthermore, mRNA profiling of individual POA and MGE interneurons will help to identify novel subtype specific transcripts, potentially useful as molecular and physiological marker. Taken together, this project intends to reveal the contribution of epigenetic transcriptional regulation to interneuron subtype development and cortical function.

• DFG Programme: Research Grants
• Participating Persons: Dr. Natja Haag; Dr. Lutz Liebmann, Ph.D.; Professor Dr. Tomas Pieler
• Ehemaliger Antragsteller: Professor Dr. Christian Andreas Hübner, from 5/2013 until 5/2014