Role of Complement in Neural Crest migration and craniofacial development

颅面疾病是婴儿死亡的主要原因，并具有严重的终身后果，对儿童和父母都是毁灭性的。颅面畸形通常被认为是面部基础结构的异常，如骨和软骨发育异常。面部骨骼和软骨起源于一种称为神经嵴的细胞群，在胚胎发育期间，神经嵴从后脑勺迁移形成面部。因此，颅面疾病通常归因于神经嵴发育的问题。有大量的各种颅面异常有遗传起源，但只有在少数情况下已被确定的突变基因。此外，只有在极少数情况下，受影响基因的功能是已知的。在这个项目中，我们建议使用动物模型，适合遗传解剖研究基因，可能涉及颅面畸形。该项目产生的数据将直接用于后续研究，以测试等同基因的突变是否会导致人类颅面畸形。为了找到这些新的基因，我们从其他系统中推断出知识，其中细胞迁移被更好地理解，如免疫系统。我们的初步数据表明，一个很好的特征免疫反应途径，称为补体，可能在神经嵴迁移中发挥关键作用。补体级联被免疫系统用来控制感染和破坏微生物。我们的观察结果表明，补体级联反应的特定元素的突变导致神经嵴迁移的显着缺陷。在这个项目中，我们建议确定这些因素控制神经嵴发育的细胞和分子机制。尽管补体缺乏是患者中相对常见的问题，但该系统在胚胎发育中的作用，更不用说在颅面疾病中的作用，已被完全忽视。这将是第一次在胚胎发育的早期阶段，即在胚胎中存在任何血液或血管之前，涉及补体因子。了解补体在神经嵴迁移中的作用将是了解某些先天性颅面缺陷起源的前奏，并将为制定预防策略和修复治疗提供可能性。重要的是，补体系统在正常颅面形成中发挥作用的证明将对卫生政策产生深远的影响。我们的研究结果可能表明，孕妇在妊娠早期应避免补体抑制剂治疗（治疗自身免疫性疾病）。这些可能会对孩子造成毁灭性的后果，相当于过去使用沙利度胺。

Craniofacial disorders are a primary cause of infant mortality and have serious lifetime consequences, devastating for both children and parents. Craniofacial malformations are usually recognized as abnormalities in the underlying structure of the face, such as anomalies in bone and cartilage development. Facial bones and cartilages originate from a cell population called the neural crest, which migrates from the back of the head to form the face during embryonic development. Therefore, craniofacial disorders are usually attributed to problems in neural crest development. There is a large variety of craniofacial anomalies which have a genetic origin but in only a few cases have the mutated genes been identified. Moreover, only in an extremely small proportion of these cases is the function of the affected gene known. In this project we propose to use animal models that are amenable to genetic dissection to study genes that are potentially involved in craniofacial malformations. The data generated in this project will be directly used in subsequent research to test whether mutations in equivalent genes lead to craniofacial anomalies in humans. In order to find these new genes we have extrapolated knowledge from other systems in which cell migration is better understood, as the immune system. Our preliminary data suggests that a well characterised immune response pathway, called complement, may play a key role in neural crest migration. The complement cascade is used by the immune system to control infections and destroy microbes. Our observations show that mutations in specific elements of the complement cascade lead to dramatic defects on neural crest migration. In this project we propose to identify the cellular and molecular mechanisms by which these factors control neural crest development. In spite of complement deficiencies being a relatively common problem in patients, the role of this system in embryonic development, let alone in craniofacial disorders, has been completely neglected. This will be the first time to implicate complement factors in the early phases of development, before any blood or vessels are present in the embryo. Understanding the role of complement in neural crest migration will be a prelude to understanding the origins of some congenital craniofacial defects, and will open the possibility to develop prevention strategies and repair therapies. Importantly, the demostration that the complement system plays a role in normal cranofacial formation will have a profound impact in health policy. The results from our research may suggest that pregnant women should avoid complement inhibitors treatments (to treat autoimmune diseases) during early gestation. These could have devastating consequences for the child, equivalent to the use of thalidomide in the past.