Förderung 2016

"The epigenetic modulation of cortical interneuron survival by the DNA- methyltransferase 1 (DNMT1) over life time"

Summary

Age-related constraints, like cognitive decline, deficits in sensory perception and motor performances of elderly, rather rely on structural and functional defects of particular neuronal cell- types than an overall neuronal loss. Dysregulated gene expression is thought to contribute to age- associated neuronal impairments, which in turn depend on genetic and epigenetic factors  [1].

Epigenetic gene regulation by DNA methylation, executed by DNA-methyltransferases (DNMTs), and histone modifications seem to be critical for the maintenance of neuronal health and function throughout the entire lifespan [3]. Our previous data provide evidence that in the mouse model system DNMT1 function is associated with a vulnerability of inhibitory cortical interneurons towards aging, which constitute essential key players of information processing in the cerebral cortex. Additionally, DNMT1 seems to be required for normal interneuron function in young mice, suggesting stage-dependent modes of action. In addition to DNA methylation, DNMTs interact with histone modifications, enabling various facets of epigenetic gene regulation [5]. Hence, the ultimate goal of this proposal is to approach the diverse DNMT1-dependent epigenetic mechanisms of transcriptional control that contribute to the loss of cortical interneurons in aged mice by integrating its function in modulating neuronal activity over life time.

Project-related publications

Zimmer G, Garcez P, Rudolph J, Niehage R, Weth F, Lent R, Bolz J. Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons. Eur J Neurosci 2008; 28:62-73.
Zimmer G, Schanuel SM, Burger S, Weth F, Steinecke A, Bolz J, Lent R. Chondroitin Sulfate Acts in Concert with Semaphorin 3A to Guide Tangential Migration of Cortical Interneurons in the Ventral Telencephalon. Cerebral Cortex 2010; (10):2411-22
Rudolph J, Zimmer G, Steinecke A, Barchmann S, Bolz J. Ephrins guide migrating cortical interneurons in the basal telencephalon. Cell Adh Migr 2010; 4.
Zimmer G, Rudolph J, Landmann J, Gerstmann K, Steinecke A, Gampe C and Bolz J. Bidirectional ephrinB3/EphA4 signaling mediates the segregation of MGE‑and POA derived interneurons in the deep and superficial migratory stream. J Neurosci 2011; 31(50):18364-80.
Rudolph J, Gerstmann K, Zimmer G, Steinecke A, Döding A and Bolz J. A dual role of EphB1/ephrinB3 reverse signaling on migrating striatal and cortical neurons originating in the preoptic area: should I stay of g  o away? Frontiers in Cellular Neuroscience. 2014 July; 18 (8)
Steinecke A, Gampe C, Zimmer G, Rudolph J, Bolz J. EphA/ephrin-A Reverse Signaling Promotes the Migration of MGE-derived Cortical Interneurons. Development. 2014 Jan;141(2):460-71.
Rüdiger T, Zimmer G , Barchmann S, Castellani V, Bagnard D and Bolz J. Integration of opposing semaphorin guidance cues in cortical axons. Cerebral Cortex 2013 Mar;23(3):604‑14
Blümel L, Pensold D, Khundadze M and Zimmer G. Curbing Methylation: A Key to Eternal Youth And Vigor?International Journal of Neural Science and Brain Research. 2014 August.
Gerstmann K, Pensold D, Symmank J, Khundadze M, Hübner Ch, Bolz J and Zimmer G. Thalamic afferents influence cortical progenitors via ephrinA5/EphA4 interactions. Development. 2015 Jan 1;142(1):140-50
Gerstmann K and Zimmer G. Fine-tuning of cortical progenitor proliferation by thalamic afferents. Neural Regen Res. 2015 June 10(6):887-8
Pensold D, Symmank J, Hahn A, Rotzsch A, Haag N, Andreas N, Schubert K, Salinas-Riester G, Downie BR, Ludewig F, Hübner CA, Pieler T & Zimmer G. DNMT1 controls the migratory shape and dynamics of immature cortical interneurons. In Revision.