Does Arsenic Target Border Specific Cells during Embryogenesis?

描述（由申请人提供）：砷是一种饮用水污染物，影响着全世界数百万人。胚胎发育期间的暴露与低出生体重、运动活动改变和神经元发育减少有关，可能是因为骨骼肌细胞和神经元的数量或定位减少。事实上，我们的数据表明，亚砷酸盐暴露于干细胞衍生的胚胎样体会降低MyoD、Myf5、myogenin和NeuroD、neurogenin-1和neurogenin-2的表达，这些转录因子分别是将干细胞转化为骨骼肌细胞和感觉神经元所需的转录因子。这两种细胞类型在神经板边界指示细胞中具有共同的谱系，它们表达参与肌肉发生的转录因子，如Pax3， Pax7, Dlx5， Msx1和Msx2，并负责分泌导致神经嵴指示细胞形成的因子，神经嵴指示细胞产生感觉神经元。在接触亚砷酸盐的胚体中，Msx2表达减少，Pax3在胚样体内的空间定位发生改变。这些数据表明，神经板边界指示细胞的数量和空间定位可能在砷的发育毒性中起关键作用。这样做的目的是

DESCRIPTION (provided by applicant): Arsenic is a contaminant of drinking water that affects millions of people throughout the world. Exposure during embryonic development is associated with low birth weight, altered locomotor activity, and reduced neuronal development, likely because of reductions in the number or localization of skeletal myocytes and neurons. Indeed, our data indicate that arsenite exposure to stem cell-derived embryoid bodies reduces the expression of MyoD, Myf5, myogenin, and NeuroD, neurogenin-1, and neurogenin-2, all transcription factors needed to convert stem cells into skeletal myocytes and sensory neurons, respectively. Both of these cell types share a common lineage in the neural plate border specifier cells, which express transcription factors involved in myogenesis, such as Pax3, Pax7, Dlx5, Msx1, and Msx2, and are responsible for secreting factors that lead to the formation of the neural crest specifier cells, which produce sensory neurons. In embryonic bodies exposed to arsenite, Msx2 expression is reduced and Pax3 spatial localization within the embryoid body is altered. These data suggest that the number and spatial localization of neural plate border specifier cells may play a critical role in the developmental toxicity of arsenic. The goal of this application is to determine whether arsenic alters the number and/or localization of neural plate border specifier cells and to determine the specific inductive or repressive signaling pathway targeted by arsenic during the formation of the neural plate, neural crest, and the mesoderm. In the first aim, we will examine changes in the localization and number of the neural plate border specifier cells following exposure to arsenic or its methylated metabolites. These results will enable us to both determine if the specifier cells are altered, and also determine whether neural crest cell production is inhibited. The goal of the second aim is to determine the inductive and repressive signaling pathways that are targeted by arsenic. Specifically, we will use Wnt1, Wnt3, Wnt3a, Wnt5a, noggin, Bmp2, and Bmp4 to differentiate the embryonic stem cells and investigate whether arsenic abrogates sensory neuron and skeletal myotube formation. Our long-term objective is to understand why arsenic-exposed populations are at increased risk for defects in skeletal muscle and neuronal development, and how this leads to functional changes such as low birth weight and altered neuronal function. We can then use this generated data to investigate the specific mechanisms by which arsenic alters the development of neural crest cells and paraxial mesoderm.