It has long been a goal of neurobiologists to understand the mechanisms that regulate development of the mammalian forebrain, as the forebrain is often referred to as the structure whose complexity sets humans apart from other higher-order organisms. To date, numerous signaling pathways have been implicated in the proper patterning and development of the forebrain primordium, the prosencephalon. However, how these pathways are regulated at the molecular level is largely unclear. The retinoic acid (RA) signaling pathway is one such pathway. Though it is clear that retinoic acid signaling is required for proper development of the forebrain, it is unclear how cell type-specific responses to RA are modulated. Additionally, because of redundancy in RA-synthesizing enzymes and RA receptor molecules, it has been difficult to investigate the effects of regional loss of RA-dependent gene transcription. The goal of this study is to utilize a mouse line lacking enzymatic activity of the histone acetyltransferase Gcn5 (Gcn5hat) to better understand the role of RA signaling in border specification in the developing forebrain. Gcn5hat mutants display ectopic structures in the dorsal telencephalon that express thalamic markers, suggesting a massive rostral expansion of the dorsal diencephalon. Gcn5 has been previously implicated in regulating RA signaling and it has been hypothesized that rostral expansion of the developing thalamus is limited by localized dorsal production of RA. Preliminary data suggests that Gcn5 regulates RA signaling through non-epigenetic mechanisms, which calls into question the prevailing hypothesis that Gcn5-mediated histone acetylation is required to promote RA-dependent gene expression. This study aims to address two fundamental questions relating to Gcn5 and its role in RA-mediated forebrain development. First, I will investigate patterning and differentiation in the forebrains of Gcn5hat mutants to determine the exact role of Gcn5 in forebrain development. More specifically, it will determine the requirement of Gcn5 acetyltransferase activity for specifying the proper borders between forebrain structures and will also determine whether these structures go on to produce their appropriate neuronal subtypes. Second, this study will test the hypothesis that Gcn5 acetyltransferase activity is required for proper RA signaling in the developing forebrain and I will determine whether the developmental phenotypes can be modulated by changes in dietary RA levels. Lastly, this study will investigate the molecular mechanism by which Gcn5 regulates RA signaling. I will test the novel hypothesis that Gcn5 promotes RAR-mediated signaling via acetylation of TACC1. This investigation will broaden our understanding of how Gcn5 elicits tissue-specific signaling responses through novel, non-epigenetic mechanisms. Together, these experiments will shed light on new functions of a developmentally critical acetyltransferase, increase our understanding of RA signaling in forebrain development, and identify specific neurodevelopmental processes that require Gcn5, potentially implicating Gcn5 in human developmental, cognitive, and neuropsychiatric diseases.
This project aims to gain insight into the molecular mechanisms regulating development of the mammalian central nervous system through vitamin A-dependent mechanisms. Investigating these mechanisms in neural stem cells and mouse embryos will help us better understand how development normally occurs and what goes wrong in neurodevelopmental diseases. Gaining a deeper understanding of neural stem cell biology will therefore aid researchers in the development of new therapies for neurodegenerative diseases, traumatic brain and spinal cord injuries, and neurodevelopmental disorders.
|Wilde, Jonathan J; Siegenthaler, Julie A; Dent, Sharon Y R et al. (2017) Diencephalic Size Is Restricted by a Novel Interplay Between GCN5 Acetyltransferase Activity and Retinoic Acid Signaling. J Neurosci 37:2565-2579|