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The Role of Lysine Acetyltransferase Tip60 in the Murine Hippocampus

dc.contributor.advisorEichele, Gregor Prof. Dr.
dc.contributor.authorUrban, Inga
dc.titleThe Role of Lysine Acetyltransferase Tip60 in the Murine Hippocampusde
dc.contributor.refereeEichele, Gregor Prof. Dr.
dc.description.abstractengMaking new memories is a highly complex process, which involves rapid modifications of existing proteins, induction of gene expression, de novo protein synthesis, and the altering of neuronal structures. The cellular machinery involved in these processes has been the subject of numerous studies, which have contributed enormously to our understanding of memory formation. Posttranslational modifications (PTMs), such as phosphorylation and acetylation, are essential for memory formation. They are an integral part of signaling cascades and regulate the accessibility of genes for transcription. By providing functional and structural plasticity they can regulate both a protein’s stability and its interactions with other proteins. PTMs tend to be rapid and transient, allowing for highly dynamic regulation of protein function as is required for the formation of new memories. Lysine acetylation is implicated in synaptic plasticity as well as memory formation. This PTM has mostly been studied with histone protein substrates and contributes to the opening of chromatin for active transcription. The acetylation state of proteins is regulated by two enzyme classes of opposing activity: lysine acetyltransferases add acetyl groups to lysine residues of proteins, while lysine deacetylases remove them. This work is focused on lysine acetyltransferase TIP60/KAT5, for which numerous histone as well as non-histone substrates have already been identified. However, its function in the mammalian nervous system is largely unknown. The aim of this thesis project is therefore to begin to elucidate the role of TIP60/KAT5 in the mammalian brain. The hippocampus is chosen as a region of interest since it has a well-established role in the encoding of new memories both in rodents and humans. Directing Tip60 deletion to excitatory neurons in the hippocampus in two different mouse models, the obtained results show that TIP60-deficiency leads to a constitutive upregulation of several immediate-early genes, predominantly restricted to the CA1 region. One of these genes – Npas4 – is known to be involved in the regulation of inhibitory synapse formation. While the conditional knockout mice appear normal the first weeks after gene deletion they become prone to seizures later on, consistent with a progressive effect on synaptic homeostasis. Subjecting these mice to a series of behavioral studies reveals modest changes in memory functions. Moreover, by analyzing the transcriptome of hippocampal subregion CA1 using next generation sequencing, a marked change in the expression of genes involved in synaptic function is identified. The findings presented here provide first insights into the function of TIP60 in the mouse hippocampus and indicate a role in the maintenance of hippocampal network
dc.contributor.coRefereeFischer, André Prof. Dr.
dc.contributor.thirdRefereeFischle, Wolfgang Dr.
dc.subject.enghistone acetylationde
dc.subject.englearning and memoryde
dc.subject.engimmediate-early genesde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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