Charakterisierung der Bedeutung von Sp-Transkriptoren in neuronen-spezifischen Genexpression

基因表达的细胞类型特异性控制对大脑发育和功能至关重要。许多神经元特异性启动子含有GC盒元件，这对神经元中许多基因的表达至关重要。通过GC盒的序列特异性转录控制主要由Sp转录因子决定。它们与癌症和神经退行性疾病等疾病中涉及的许多不同基因的调节有关，然而，神经元的调节和活动知之甚少。本项目将重点研究Sp转录因子在神经元特异性基因表达中的作用。作为一个模型，我们将研究细胞周期蛋白依赖性激酶5激活因子p35的表达。Gill实验室先前的工作表明，p35启动子包含一个重复的GC盒元件，该元件对于神经元特异性表达是必要的和充分的，并且在体外与Sp蛋白结合。我们将描述个体Sp转录因子与p35启动子在体内的相互作用及其对神经元分化的影响。此外，我们打算鉴定Sp4的新的神经元靶基因，与Spl和Sp3不同，Sp4主要在发育中的神经系统中表达。我们假设Sp4通过结合和激活p35启动子和其他启动子中含有GC box元件的神经元特异性基因，在神经元的分化和功能中发挥重要作用。

The cell type specific control of gene expression is critical for brain development and function. Many neuron-specific promoters contain GC box elements, which are important for expression of numerous genes in neurons. The sequence specific transcriptional control via GC boxes is largely determined by Sp transcription factors. They have been implicated in the regulation of many different genes involved in diseases like cancer and neurodegenerative diseases, nevertheless the regulation and activity in neurons is poorly understood. This project will focus on the role of Sp transcription factors in neuron specific gene expression. As a model we will investigate the expression of the cyclin dependent kinase 5 activator p35. Previous work by the Gill lab has shown that the p35 promoter contains a repeated GC box element that is necessary and sufficient for neuron specific expression and is bound by Sp proteins in vitro. We will characterize the interaction of individual Sp transcription factors with the p35 promoter in vivo and their effect on neuronal differentiation. Furthermore, we intend to identify new neuronal target genes of Sp4, which in contrast to Spl and Sp3, is expressed predominantly in the developing nervous system. We hypothesize that Sp4 plays an important role in differentiation and function of neurons through binding and activation of p35promoter and other neuron-specific genes containing GC box elements in their promoters.