Neuronal morphogenesis during development, including neuronal migration, polarization, axon growth/guidance, and dendrite development, are crucial steps for forming the functional neural circuits. Disruption in these processes underlies many neurodevelopmental disorders. Similar neuronal morphogenesis steps are required in adult nervous system after injuries to regenerate and restore damaged neural circuits. Unfortunately, neurons in the mammalian central nervous system (CNS) lose their intrinsic ability to support neural regeneration. Coordinated regulation of gene expression not only controls neuronal morphogenesis during development, but also underlies the loss of intrinsic regeneration ability of mature CNS neurons. Epigenetic regulation, including DNA methylation and histone modification, is becoming a major cellular mechanism for regulation of gene expression. To date, however, very few studies have investigated how neuronal morphogenesis during neural development and regeneration is regulated at the epigenetic level. Two recent studies have identified the histone methyltransferase EZH2, which methylates histone 3 at lysine 27 (H3K27), as the mutant gene that causes the Weaver Syndrome, a developmental disorder showing intellectual disability and enlarged brain size (macrocephaly). Our preliminary studies have revealed that EZH2 is highly expressed in post-mitotic neurons during development. Functionally, EZH2 is necessary for axon growth of developing cortical neurons, and regulates several neuronal morphogenesis-associated genes, such as Slit2 and Pten. Moreover, conditional deletion of EZH2 in differentiated neurons seems to result in bigger brain. In the adult nervous system, the level of EZH2 is very low in the CNS. However, it is drastically up regulated in adult sensory neurons upon peripheral nerve injury, together with down regulation of H3K27 demethylases JMJD3/UTX. Functionally, knocking down EZH2 impairs sensory axon regeneration both in vitro and in vivo, probably through up regulation of Pten and KLF4, two well-known repressors of neural regeneration. Conversely, ectopically down regulation of the demethylase JMJD3 is sufficient to promote axon regeneration in vivo. Based on these results, we hypothesize that during neural development EZH2 and H3K27 methylation are key epigenetic regulators of neuronal morphogenesis, and in the adult nervous system they function to support the intrinsic neural regeneration ability through repressing neural regeneration repressors. In this proposed study we will 1) investigate the roles of EZH2 in regulation of neuronal morphogenesis during development by conditionally knock out or overexpress EZH2 in post- mitotic neurons, 2) investigate if regulation of H3K27 methylation by EZH2 and JMJD3/UTX is necessary and sufficient for mammalian axon regeneration, and 3) elucidate the molecular mechanisms by which EZH2 and H3K27 methylation regulate gene expression during development and regeneration.
Neuronal morphogenesis is important not only during development for forming the neural circuitry, but also after nerve injuries for recovering neural functions. The proposed study will investigate the roles of histone methylation, regulated by methyltransferase EZH2 and demethylases JMJD3/UTX, in controlling neuronal morphogenesis during development and regeneration. The study will help us not only reveal novel mechanisms underlying neurodevelopmental disorders, such as the Weaver Syndrome, but also find new approaches to promote neural regeneration after spinal cord or brain injuries.
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