Function and regulation of Lhx genes in craniofacial development

颅面畸形涉及第一鳃弓衍生物，包括颌骨，腭，和牙齿，是一个 这是人类出生缺陷的主要类型。了解颅面的分子遗传机制 发展对于制定诊断、预防和治疗人类疾病的创新方法至关重要。 缺陷niy研究的长期目标是描述控制 第一鳃弓的发育，通过鉴定转录因子和顺式调节元件 重要的是在这个过程中，并确定他们的层次关系。Lhx 6和Lhx 3基因，编码 同源结构域转录因子是第一鳃弓发育的主要调节因子;小鼠突变体 缺乏Lhx 6和Lhx 8的活性，出生时有腭裂，没有磨牙。我特别 发现Lhx基因对于臼齿和第二腭发育的初始步骤是必需的。两 Lhx基因在颅面发育中的功能和调控仍然存在关键问题：1）Lhx基因在颅面发育中的作用是什么？ Lhx在牙齿和腭发育起始过程中的分子和细胞机制， 第一鳃中Lhx基因表达的上游调控因子是什么 拱？我在ROO阶段的研究将使用小鼠突变模型以及 生物化学和分子生物学方法。该项目的结果将提供以下方面的重要信息： Lhx 6和Lhx 8功能和表达的破坏如何导致人类颅面缺陷。

Craniofacial abnornialities involving the first branchial arch derivatives, including jaw,,palate, and teeth, are a major class of birth defects in humans. Understanding the molecular genetic mechanisms behind craniofacial development is vital to devising innovative methods for diagnosis, prevention, and treatment of human defects. The long-term goal of niy research is to characterize the transcriptional network that governs development of the first branchial arch, by identifying transcription factors and cis-regulatory elements important in this process, and determining th^eir hierarchic^ relationship. Lhx6 and Lhx3 genes, encoding homeodomain transcription factors, are major regulators of first branchial arch development; mouse mutants lacking the activities of both Lhx6 and Lhx8 are born with cleft secondary palate and no molars. Specifically, I found that the Lhx genes are essential for the initial steps of molar and secondary palate development. Two crucial questions remain on the function and regulation of Lhx genes in craniofacial development: 1) what is the molecular and cellular mechanisms of Lhx function during the initiation of tooth and palate development?, and 2) what are the upstream factprs that regulate the expression of the Lhx genes in the first branchial arch? My research during'ROO phase will address these questions using mouse mutant models as well as biochemistry and molecular biology methods. The results of this project will provide critical information on how disruption in Lhx6 and Lhx8 function and expression can contribute to human craniofacial defects.