Scrutinize bHLH transcription factors mediated organ of Corti cell fate determina

摘要： 基本螺旋环螺旋转录因子对内耳神经感觉至关重要 发育：Atoh1调节毛细胞和Neurog1的分化 和Neurod1分别调节神经元的规格和分化。 Delta和锯齿状配体在Hcs和Notch受体中的表达 支持细胞(SCs)引导支持细胞分化。此外，可扩散的 来自毛细胞和其他来源的因子巩固了拓扑上的正确性 差异化。人类听力障碍可能导致HCS不可逆转的丧失 和SCS。重建Corti(OC)器官需要在拓扑上正确 两种类型的毛细胞，内毛细胞(IHC)和外毛细胞(OHC)，AS 以及几种类型的SC。特定细胞类型在右侧如何区分 地点未知。BHLH基因Neurod1的缺失导致早产儿， Atoh1的异常表达。伴随着一种改变的神经1的丧失 Atoh1的表达导致某些外毛细胞的转化 进入内毛细胞(IHC)。在Aim1a中，我将在Neurod1缺失的小鼠中进行关联， Atoh1-Cre介导的R26-YFP报告基因Atoh1的表达 Delta-Notch效应分子(Hes1、Hes5、Hey2)及其可扩散分子的表达 (Fgf8、Fgf10、FGF20、BMP4)。在Aim2a中，我将分析一种新的鼠标模型 Neurog1与Atoh1-Cre(Atoh1-Cre)结合的错误表达 Cre；Atoh1f/kiNeurog1)。在Aim2b中，我将调查Neurod1在 与Neurog1(Atoh1-Cre；Atoh1f/kiNeurog1； Neurod1-/-)将影响某些HC标记并改变脑内Delta-Notch模式 OC。这些突变体将批判性地测试假定的分子因果关系 调控OC模式的机制，包括HC和SC 区分，超越相关证据，不能区分 拓扑和单元特定效果。

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.