| dc.description.abstracteng | In living organisms, a molecular clockwork synchronises physiological mechanisms with daily recurrent changes in the environment, a process that is termed entrainment. The two basic helix-loop-helix (bHLH) transcription factors SHARP1 (DEC2) and SHARP2 (DEC1, Stra13) are important amplitude modifiers of this clockwork. Both factors play important roles in the adaptation to altered light/dark cycles and in the homeostatic control of sleep. Moreover, sleep/wake and behavioural analysis of SHARP1 and -2 double mutant (S1/2-/-) mice revealed characteristic features reminiscent of psychiatric endophenotypes. Unexpectedly, microarray analysis identified genes encoding myelin proteins among sleep/wake-dependent transcripts in the cerebral cortex of wild type (WT) mice, whereas this regulation appeared to be attenuated in S1/2-/- animals. Thus, a major aim of this thesis was to corroborate these findings with more precise sampling procedures, including a high spatial and temporal resolution. Laser-captured microdissection (LCM), together with quantitative RT-PCR was applied to analyse a potential circadian and/or activity-dependent pattern of myelin gene expression in precisely defined forebrain areas in WT mice as well as a deregulation in S1/2-/- mice. Indeed, I detected a novel plasticity of myelin genes on mRNA level which appeared to be time- and region-specific in WT animals. This finding is of particular interest as adult plasticity of white matter tracts was recently discussed in response to learning. However, these effects were attenuated in S1/2-/- mice. Intriguingly, a deregulation of myelin genes is also reported for psychiatric diseases like schizophrenia, bipolar disorder and depression. S1/2-/- mice also showed an attenuated response of some myelin genes upon sleep deprivation, which potentially reflects the function for SHARP proteins as homeostatic integration factors both in mice and humans. The expression of myelin genes was also reduced in stimulated primary cultured oligodendrocytes isolated from S1/2-/- mice, thus reflecting the in vivo findings. Consistently, overexpressed SHARP proteins activated Mal and Mbp promoters, as shown in luciferase reporter gene assays in Oli-neu cells and primary oligodendrocytes.
In summary, myelin gene expression for the first time was analysed in precise cortical regions indicating a novel high plasticity. In S1/2-/- mice, these effects were reduced, potentially as SHARP proteins are integration factors that exert both repressive and co-activating functions in a context-specific manner. By linking alterations in the homeostatic processes to the etiology of psychiatric diseases the S1/2-/- mouse model might contribute to the understanding of mental disorders. | de |