Regulation of border specification in the developing forebrain by Gcn5-mediated r

描述（由申请人提供）：长期以来，神经生物学家的目标是了解调节哺乳动物前脑发育的机制，因为前脑通常被称为其复杂性使人类有别于其他高级生物体的结构。到目前为止，许多信号通路已被牵连在正确的模式和前脑原基，前脑的发展。然而，这些途径在分子水平上是如何调节的，在很大程度上还不清楚。视黄酸（RA）信号通路就是这样一种通路。虽然很清楚视黄酸信号传导是前脑正常发育所必需的，但尚不清楚细胞类型特异性对RA的反应是如何调节的。此外，由于RA合成酶和RA受体分子的冗余，很难研究RA依赖性基因转录的区域损失的影响。本研究的目的是利用缺乏组蛋白乙酰转移酶Gcn5（Gcn5hat）的酶活性的小鼠系，以更好地了解RA信号在发育中的前脑中的边界规范的作用。Gcn5hat突变体显示异位结构，在背侧端脑表达丘脑标记，这表明一个巨大的吻侧扩张的背侧间脑。GCN 5以前已经涉及调节RA信号传导，并且已经假设发育中的丘脑的吻侧扩张受到RA的局部背侧产生的限制。初步数据表明，Gcn5调节RA信号通过非表观遗传机制，这就质疑了流行的假设，即Gcn5介导的组蛋白乙酰化是促进RA依赖性基因表达所必需的。 本研究的目的是解决两个基本问题，有关GCN 5和它的作用，RA介导的前脑发育。首先，我将研究Gcn5hat突变体前脑的模式和分化，以确定Gcn5在前脑发育中的确切作用。更具体地说，它将确定Gcn 5乙酰转移酶活性的要求，以指定前脑结构之间的适当边界，并确定这些结构是否继续产生其适当的神经元亚型。其次，本研究将测试的假设，GCN 5乙酰转移酶活性所需的适当的RA信号在前脑的发展，我将确定是否发育表型可以调节饮食中的RA水平的变化。最后，本研究将探讨Gcn5调节RA信号的分子机制。我将测试新的假设，即Gcn5通过乙酰化TACC1促进RAR？介导的信号传导。这项研究将拓宽我们对Gcn5如何通过新的非表观遗传机制激发组织特异性信号应答的理解。总之，这些实验将揭示一种对发育至关重要的乙酰转移酶的新功能，增加我们对前脑发育中RA信号传导的理解，并确定需要Gcn 5的特定神经发育过程，可能涉及Gcn 5在人类发育，认知和神经精神疾病中的作用。

DESCRIPTION (provided by applicant): 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.