Neurogenic plasticity and brain development

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A long-term goal of my research program is to understand how an animal's experience in the environment influences brain development. NSERC-funded research from my lab showed that sensorimotor experience, such as movement or vision, maintains high levels of neurogenesis in the zebrafish larval brain. Larvae that swim the most in normal ambient light cycles exhibit increased brain growth over subsequent days of development. In contrast, movement restraint or dim light cycles lead to reduced brain growth. We observed that sensorimotor deprivation resulted in neural stem cells (NSCs) undergoing premature neuronal differentiation, with fewer neurons generated over time. Thus, NSCs appear to change their fate in response to altered sensorimotor stimuli, but the intrinsic mechanism underlying this neurogenic plasticity is unresolved and is the focus of this proposal. Cell fate decisions in NSCs are strongly influenced by epigenetic modifications such as chromatin methylation, and the enzyme Ehmt2 is a key regulator of this process by turning NSC genes off so that stem cells can differentiate into neurons. We generated an Ehmt2 loss of function mutant using CRISPR/Cas9 gene editing and asked whether this gene is required to mediate experience-dependent neurogenic plasticity responses of NSCs. Preliminary data indicates that neurogenesis is not altered in the Ehmt2 mutant in response to movement restraint, suggesting that loss of Ehmt2 prevents the plasticity response in the brain normally elicited by sensorimotor deprivation. Our novel mutant model provides a paradigm for testing hypotheses regarding the regulation of NSC cell fate and likewise for linking neurogenic plasticity to patterns of epigenetic modification within NSCs. The objective of this proposal is to investigate whether an altered movement experience causes NSCs in the postembryonic zebrafish pallium to change their fate due to epigenetic silencing of NSC genes. The following three specific research aims are designed to address this objective: Aim 1: To examine how Ehmt2 loss of function alters experience-dependent neurogenic plasticity. Genetic lineage tracing will test whether mutant NSCs fail to provide a normal plasticity response to movement restraint, by enhancing self-renewal instead of promoting differentiation. Aim 2: To evaluate the degree to which neurogenic plasticity requires Ehmt2-dependent silencing of NSC gene expression. We will interrogate how loss of Ehmt2 leads to transcriptome changes in NSCs under normal or movement restrained conditions. Aim 3: To determine the impact of enhanced Ehmt2 expression on neurogenic plasticity. Increased Ehmt2 activity will test if enhanced chromatin methylation prevents expansion of NSCs when movement is increased, and instead promotes differentiation. This research will help to elucidate mechanisms of experience-dependent neurogenic plasticity for a deeper understanding of gene-by-environment interactions in brain development.