Tip60 HAT action is critical for neuronal development and plays a neuroprotective role in early neurodegenerative progression

Abstract

Epigenetic mechanisms of gene control via histone acetylation regulate neuronal patterning and activity during neurogenesis that influence cognitive function. It remains unclear; however, which specific histone acetyltransferase (HAT) enzymes control these processes. The HAT Tip60 functions in chromatin-mediated processes including gene regulation and cell cycle control, with emerging roles in neuronal function. We previously reported that Tip60 HAT activity is required for the transcriptional control of genes involved in early neuronal development, essential for proper neurogenesis during development, and highly localized to the embryonic neuropil and median cells which later form the central nervous system and motor neurons, respectively. Here, we investigate a role for Tip60 in cell cycle control during nervous system development using Drosophila larval brain neuroblasts (NB) as a well characterized model. We show that loss of Tip60 HAT activity in the nervous system of the fly alters cell cycle progression of mitotic neuroblasts in the larval brain. Additional clonal analysis using novel MARCM fly lines carrying Tip60 wild-type and HAT defective constructs reveals a critical role for Tip60 in the appropriate regulation of neuroblast proliferation in the larval brain. Importantly, chromatin immunoprecipitation and real-time PCR experiments in larval brain tissue reveal that Tip60 directly regulates genes important for cell cycle control, several of which are critical for neural stem cell renewal and differentiation. These observations provide insight into understanding epigenetic HAT based mechanisms underlying early nervous system development and function and have implications for epigenetic mechanisms in specific neural circuits such as motor neuron function. The HAT Tip60 is implicated in Alzheimer's disease (AD) via its formation of a transcriptional regulatory complex with the amyloid precursor protein (APP) intracellular domain (AICD). As epigenetic transcriptional regulatory mechanisms such as histone acetylation are critical for proper neuronal function, it is postulated that their misregulation might be linked to early pathophysiological mechanisms that contribute to AD. Disruption of APP function is associated with axonal transport defects and axonopathies, raising the possibility that an epigenetic role for Tip60 might also be involved. Here, we examine whether Tip60 HAT activity functions in axonal transport using Drosophila CNS motor neurons as a well characterized transport model. We show that reduction of Tip60 HAT activity in the nervous system causes axonopathy and transport defects associated with epigenetic misregulation of certain axonal transport linked Tip60 target genes. Functional consequences of these defects are evidenced by reduced locomotion activity of the mutant Tip60 larvae and these phenotypes can be partially rescued with certain HDAC inhibitors. Finally, we demonstrate that Tip60 function in axonal transport is mediated by APP and that remarkably, excess Tip60 exerts a…