Craniofacial Development and Disease

描述(申请人提供)：为了最大限度地减少和预防颅面畸形，了解个别畸形综合征的具体原因是至关重要的。然而，这需要深入了解在胚胎发育过程中塑造头部和面部发育的正常发育事件。头部和面部的大部分组织，包括骨、软骨、结缔组织和周围神经系统组织，都来自一种称为神经脊的细胞群。大多数颅面综合征被认为是由于胚胎发育过程中神经脊细胞发育的缺陷所致。因此，有必要研究神经脊细胞是如何以及何时形成的，是什么引导神经脊细胞到达它们的最终目的地，是什么让神经脊细胞存活，以及神经脊细胞是如何决定成为结缔组织和神经组织的软骨或骨的。在这项建议中，我们研究了Treacher Collins综合征的小鼠模型，该模型复制了人类严重的颅面部疾病。Treacher Collins综合征是由于胚胎发育过程中发生的发育缺陷引起的，在胚胎发育过程中，神经脊细胞的生成不足，无法形成正常的头部和面部。我们已经确定了一个广泛的机制，通过它我们可以防止Treacher Collins综合征典型的颅面畸形的发展，在这项建议中，我们改进了这一过程，以促进未来的临床应用。此外，由于我们的Treacher Collins综合征小鼠模型代表了少数显示神经脊细胞形成缺陷的小鼠动物模型之一，我们使用该模型来识别对神经脊细胞和颅面发育重要的新基因。在这项研究中，我们将重点放在一个名为Nr6a1的基因上，它似乎对神经脊细胞的形成过程至关重要，因此对正常的颅面发育至关重要。

DESCRIPTION (provided by applicant): In order to minimize and prevent craniofacial anomalies, it is essential to understand the specific cause of individual malformation syndromes. However, this requires a deep appreciation of the normal developmental events that shape head and facial development during embryogenesis. The majority of the tissues of the head and face including bone, cartilage, connective and peripheral nervous system tissue are derived from a cell population called the neural crest. Most craniofacial syndromes are thought to occur due to a defect in the neural crest cell development during embryogenesis. Thus it is essential to study how and when neural crest cells are formed, what guides neural crest cells to their final destinations, what keeps neural crest cells alive and also how neural crest cells decide to become cartilage or bone of connective and nerve tissue. In this proposal we study a mouse model of Treacher Collins syndrome, which replicates the severe craniofacial disorder in humans. Treacher Collins syndrome arises due to a developmental defect occurring during embryogenesis in which insufficient neural crest cells are generated to make a normal head and face. We have identified a broad mechanism by which we can prevent the development of craniofacial anomalies typical of Treacher Collins syndrome and in this proposal we refine this process to facilitate future clinical applications. In addition, since our mouse model of Treacher Collins syndrome represents one of few mouse animal models that exhibit a defect in neural crest cell formation, we have used this model to identify new genes that are important for neural crest cell and craniofacial development. For the purpose of this proposal we focus on one gene, called Nr6a1, which appears to be critical for the neural crest cell formation process and as such is essential for normal craniofacial development.