Craniofacial Development and Disease

描述（由申请人提供）：为了减少和预防颅面畸形，了解个体畸形综合征的具体原因是至关重要的。然而，这需要对胚胎发生期间形成头部和面部发育的正常发育事件有深刻的认识。头部和面部的大部分组织，包括骨骼、软骨、结缔组织和周围神经系统组织，都来自一种叫做神经嵴的细胞群。大多数颅面综合征被认为是由于胚胎发生期间神经嵴细胞发育的缺陷而发生的。因此，研究神经嵴细胞是如何以及何时形成的，是什么引导神经嵴细胞到达最终目的地，是什么使神经嵴细胞保持活力，以及神经嵴细胞如何决定成为结缔组织和神经组织的软骨或骨，是至关重要的。在本提案中，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疾病。Treacher Collins综合征是由于胚胎发生过程中产生的神经嵴细胞不足以形成正常的头部和面部而引起的发育缺陷。我们已经确定了一种广泛的机制，通过这种机制我们可以预防典型的Treacher Collins综合征颅面异常的发展，在本提案中，我们完善了这一过程，以促进未来的临床应用。此外，由于我们的Treacher Collins综合征小鼠模型是少数表现出神经嵴细胞形成缺陷的小鼠动物模型之一，我们使用该模型来鉴定对神经嵴细胞和颅面发育重要的新基因。为了这个建议的目的，我们把重点放在一个叫做Nr6a1的基因上，它似乎对神经嵴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.