Scrutinize bHLH transcription factors mediated organ of Corti cell fate determina

摘要： 碱性螺旋环螺旋转录因子对内耳神经感觉至关重要 发育：Atoh 1调节毛细胞（HC）和Neurog 1的分化 和Neurod 1分别调节神经元的特化和分化。 HC中Delta和Jagged配体和Notch受体在大肠癌中的表达 支持细胞（SC）引导支持细胞分化。此外，可扩散 来自毛细胞和其他来源的因素巩固拓扑正确 分化人类的听力缺陷会导致HC的不可逆损失 和SC。Corti器官（OC）的重建需要拓扑正确 组织的两种类型的毛细胞，内（IHC）和外（OHC）毛细胞，作为 以及几种类型的SC。特定的细胞类型如何在右侧分化 地点不明。bHLH基因Neurod 1的缺失导致早产， Atoh 1的异常表达。Neurod 1的缺失与改变有关 Atoh 1的表达导致一些外毛细胞（OHC）的转化， 内毛细胞（IHC）。在Aim 1a中，我将在Neurod 1 null小鼠中进行关联， 使用Atoh 1-Cre介导的R26-YFP报告基因表达Atoh 1， Delta-Notch效应子（Hes 1、Hes 5、Hey 2）和可扩散分子的表达 (Fgf8、Fgf 10、Fgf 20、BMP 4）。在Aim 2a中，我将分析一种新的小鼠模型， 错误表达Neurog 1与“自终止”Atoh 1-Cre（Atoh 1-Cre）的组合， Cre; Atoh1f/kiNeurog1）。在Aim 2b中，我将研究神经元1的缺失是如何在 与Neurog 1的错误表达（Atoh 1-Cre; Atoh 1f/kiNeurog 1; Neurod 1-/-）将影响某些HC标记物，并改变细胞中的Delta-Notch模式。 OC.这些突变体将严格测试假定的分子因果关系， 调节OC模式的机制，包括HC和SC 差异，超越相关证据，无法区分 拓扑结构和细胞特异性效应。

Abstract: Basic helix loop helix transcription factors are crucial for inner ear neurosensory development: Atoh1 regulates the differentiation of hair cells (HCs) and Neurog1 and Neurod1 regulate specification and differentiation of neurons, respectively. Expression of Delta and Jagged ligands in HCs and Notch receptors in supporting cells (SCs) guides supporting cell differentiation. In addition, diffusible factors from hair cells and other sources consolidate topologically correct differentiation. Hearing defects in human can result in irreversible loss of HCs and SCs. Reconstitution of organ of Corti (OC) requires topologically correct organization of the two types of HCs, inner (IHC) and outer (OHC) hair cells, as well as several types of SCs. How specific cell types differentiate in the right location is unknown. Deletion of the bHLH gene Neurod1 results in the premature, aberrant expression of Atoh1. Loss of Neurod1 in conjunction with an altered expression of Atoh1 results in the conversion of some outer hair cells (OHCs) into inner hair cells (IHCs). In Aim1a, I will correlate in the Neurod1 null mouse, the expression of Atoh1 using Atoh1-Cre mediated R26-YFP reporter with the expression of Delta-Notch effectors (Hes1, Hes5, Hey2) and diffusible molecules (Fgf8, Fgf10, Fgf20, BMP4). In Aim2a, I will analyze a novel mouse model that misexpresses Neurog1 in combination with 'self-terminating' Atoh1-Cre (Atoh1- Cre; Atoh1f/kiNeurog1). In Aim2b, I will investigate how the absence of Neurod1 in combination with the misexpression of Neurog1 (Atoh1-Cre; Atoh1f/kiNeurog1; Neurod1-/-) will affect certain HC markers and alter Delta-Notch patterning in the OC. These mutants will critically test the presumed causalities of molecular mechanism that regulate the patterning of the OC, including HCs and SCs differentiation, beyond correlative evidence that cannot distinguish between topology and cell specific effects.