Protein/nucleic Acid Interactions In Vertebrate Embryogenesis

神经脊在脊椎动物头部、面部和颌骨的发育中起着至关重要的作用，它提供了颅面骨骼的大部分以及周围神经系统和其他颅骨组织。正常的颅面发育依赖于NC细胞及其衍生物的适当诱导、迁移和分化。这些步骤中的任何一个步骤的缺陷，无论是由于NC本身的固有缺陷，还是由于NC细胞未能与邻近组织正确地相互作用，都可能导致出生缺陷：多达三分之一的先天性畸形本质上是头面部畸形，主要是由于NC故障。我们以非洲爪蛙和淡水热带鱼Danio rerio(斑马鱼)为实验模式生物，研究NC的发育。这个项目的起点是两个转录因子，TFAP2A和DLX3，我们几年前就证明了它们的调节对于NC发展的早期步骤至关重要。 我们正在设计、建立和使用同时表达这些因子的野生型和突变型的转基因斑马鱼品系，随后进行形态和基因表达分析，以确定这些因子的靶基因，并研究它们在神经脊迁移和终末分化后期的功能。我们的目标是将TFAP2和DLX因子对特定基因的调节与人类胚胎的颅面发育联系起来，无论是正常的还是病理的，希望建立诊断工具，最终建立预防和治疗颅面畸形的治疗策略，颅面畸形是人类婴儿最常见的出生缺陷形式。

The neural crest (NC) plays a critical role in the developmental of the vertebrate head, face and jaws, providing the bulk of the craniofacial skeleton as well as peripheral nervous system and other cranial tissues. Normal craniofacial development depends on proper induction, migration and differentiation of NC cells and derivatives. Deficiencies at any of these steps, whether due to intrinsic defects in NC itself, or in failure of NC cells to interact properly with adjacent tissues, can lead to birth defects: up to a third of all congenital malformations are craniofacial in nature and mostly due to such NC failures. We have used the frog Xenopus and the freshwater tropical fish Danio rerio(zebrafish)as experimental model organisms to study NC development. The starting point for this project was two transcription factors, TFAP2a and Dlx3, the regulation of which we showed several years ago to be critical for the early steps in NC development. We are now designing, establishing and using transgenic zebrafish lines expressing both wild-type and mutated versions of these factors, followed by morphological and gene expression analysis, to identify target genes for these factors, and also to study their function in later stages of neural crest migration and terminal differentiation. Our goal is to relate the regulation of specific genes by TFAP2 and Dlx factors to cranifacial development in human embryos, both normal and pathological, hoping to establish diagnostic tools and, eventually, therapeutic strategies for preventing and treating cranifacial dysmorphology, the most common form of birth defects in human infants.