Role of Complement in Neural Crest migration and craniofacial development

补体在神经嵴迁移和颅面发育中的作用

• 批准号: MR/J000655/1
• 负责人: Roberto Mayor
• 金额: $ 48.37万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ000655%2F1
• 关键词: Role; Complement; Neural; Crest; migration

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.

颅面疾病是婴儿死亡的主要原因，并且会产生严重的终生后果，对儿童和父母来说都是毁灭性的。颅面畸形通常被认为是面部基础结构的异常，例如骨骼和软骨发育的异常。面部骨骼和软骨起源于一种称为神经嵴的细胞群，该细胞群在胚胎发育过程中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问题。有很多种颅面异常都有遗传起源，但只有少数情况下发现了突变基因。此外，只有极少数病例中受影响基因的功能是已知的。在这个项目中，我们建议使用适合遗传解剖的动物模型来研究可能与颅面畸形有关的基因。该项目产生的数据将直接用于后续研究，测试等效基因的突变是否会导致人类颅面部异常。为了找到这些新基因，我们从其他系统（例如免疫系统）中推断出了对细胞迁移有更好理解的知识。我们的初步数据表明，一种特征明确的免疫反应途径（称为补体）可能在神经嵴迁移中发挥关键作用。免疫系统利用补体级联来控制感染和消灭微生物。我们的观察表明，补体级联特定元件的突变会导致神经嵴迁移的严重缺陷。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中出现任何血液或血管之前的发育早期阶段涉及补体因子。了解补体在神经嵴迁移中的作用将成为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疗法提供可能性。重要的是，证明补体系统在正常颅面形成中发挥作用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（以治疗自身免疫性疾病）。这些可能会给孩子带来毁灭性的后果，相当于过去使用沙利度胺。

项目成果

Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo.

• DOI: 10.1083/jcb.201304051
• 发表时间: 2013-11-25
• 期刊: The Journal of cell biology
• 作者: Law AL;Vehlow A;Kotini M;Dodgson L;Soong D;Theveneau E;Bodo C;Taylor E;Navarro C;Perera U;Michael M;Dunn GA;Bennett D;Mayor R;Krause M
• 通讯作者: Krause M

Cadherin-11 mediates contact inhibition of locomotion during Xenopus neural crest cell migration.

• DOI: 10.1371/journal.pone.0085717
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Becker SF;Mayor R;Kashef J
• 通讯作者: Kashef J

In vivo collective cell migration requires an LPAR2-dependent increase in tissue fluidity.

• DOI: 10.1083/jcb.201402093
• 发表时间: 2014-07-07
• 期刊: The Journal of cell biology
• 作者: Kuriyama S;Theveneau E;Benedetto A;Parsons M;Tanaka M;Charras G;Kabla A;Mayor R
• 通讯作者: Mayor R