RPG: Molecular Mechanisms of Regulation of GAP-43 Promoter by bHLH Transcription Factors

哺乳动物神经发生的分子机制仍然难以捉摸。然而，最近，已经确定了一些指定神经元细胞命运的神经元基因。其中一些编码的转录因子含有碱性螺旋-环-螺旋（bHLH）基序。这些神经元基因分为两类：前神经基因和神经源性基因。前源性基因定义了一种状态，使细胞有能力成为神经元前体，而神经原性基因形成了一个功能网络，被认为可以将调节信号从一个细胞传递到另一个细胞，从而使成熟的神经元细胞发育。这些基因以精确的空间和时间方式被激活，以协调这一系列导致神经元分化的复杂事件。这些基因编码各种基本螺旋-环-螺旋转录因子，调节各种神经元靶基因的组织特异性转录。这些bHLH蛋白通过螺旋-环-螺旋（HLH）基序形成各种二聚体，并通过其基本结构域与特定的顺式作用元件E-box结合。根据它们的结构和表达方式，它们被划分为不同的类别。B类只能与a类bHLH蛋白形成异源二聚体，且时空表达受限。两种bHLH蛋白之间形成的异二聚体复合物的多样性为神经发生过程中不同细胞类型和发育阶段靶基因的差异转录调控提供了分子机制。大量数据表明，bHLH转录因子在神经发生过程中对决定、分化和维持事件起着至关重要的作用。然而，尚未发现特异性的神经元靶基因。本文对神经发生过程中的事件、决定、分化和维持进行了详细的研究。然而，尚未发现特定的神经元靶基因。本文详细研究了哺乳动物神经元基因GAP-43的转录调控，这是第一个被发育调节的bHLH转录因子调节的神经元基因。因此，阐明神经元bHLH转录因子与GAP-43启动子区域之间的分子相互作用将有助于更好地理解哺乳动物神经元分化以及bHLH蛋白在脑发育不同阶段协调基因表达的功能作用。

9510658 Chiaramello The molecular mechanisms underlying mammalian neurogenesis are still elusive. However recently, a number of neuronal genes that specify neuronal cell fate has been identified. Some of them encode transcription factors that contain a basic-helix-loop-helix (bHLH) motif. These neuronal genes are grouped in two specific categories: the proneural genes and the neurogenic genes. The proneural genes define a state that makes cells competent to become neuronal precursors, whereas neurogenic genes form a functional network that is thought to convey regulatory signals from one cell to the next to allow the development of mature neuronal cells. These genes are activated in a precise spatial and temporal manner in order to orchestrate this complex series of events leading to neuronal differentiation. These genes encode various basic-helix- loop-helix transcription factors that regulate tissue-specific transcription of various neuronal target genes. These bHLH proteins form various dimers through the helix-loop-helix (HLH) motif and bind to a specific cis acting element referred as E-box through their basic domain. They have been classified into distinct classes, based on their structure and pattern of expression. Class B can only form heterodimers with a class A bHLH protein and exhibit a restricted spatio-temporal expression. The variety of heterodimeric complexes formed between two bHLH proteins provides a molecular mechanism responsible for differential transcriptional regulation of target genes in different cell types and developmental stages during neurogenesis. A wealth of data demonstrates that bHLH transcription factors critically contribute to the events of determination, differentiation, and maintenance during neurogenesis. However, no specific neuronal target gene have yet been identified. This proposal deals with the detailed study of the events determination, differentiation, and maintenance during neurogenesis. However, no sp ecific neuronal target gene have yet been identified. This proposal deals with the detailed study of the transcriptional regulation of the mammalian neuronal gene, GAP-43, which is the first neuronal gene to be modulated by developmentally regulated bHLH transcription factors. Therefore, the elucidation of the molecular interactions between the neuronal bHLH transcription factors and the GAP-43 promoter region will lead to a better understanding of mammalian neuronal differentiation and the functional roles of bHLH proteins at orchestrating gene expression at different stages of brain development.