Deciphering the role of mediator of ErbB2 driven cell motility (Memo1) in regulat

破译 ErbB2 驱动的细胞运动介质 (Memo1) 在调节中的作用

基本信息

批准号：
9029313
负责人：
Eric Van Otterloo
金额：
$ 6.08万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-05 至 2017-05-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029313
关键词：
Address Affect Alleles Automobile Driving Biological Models Birth Cancer Model Cell Culture Techniques Cell Proliferation Cell physiology Cells Cellular biology Cephalic Cessation of life Congenital Abnormality Cues Defect Detection Development Disease Economic Burden Ectoderm Elements Embryo Embryonic Development Ethylnitrosourea Event Face Ganglia Genes Genetic Models Goals Growth Head Health Human In Vitro Incidence Knowledge Link Live Birth Mediating Mediator of activation protein Mesenchyme Migration Assay Modeling Mus Mutagenesis Mutation Neural Crest Neural Crest Cell Palate Pattern Pattern Formation Phenotype Play Prevention Process Proteins Quality of life Regulation Robin bird Role Secondary Palate Series Signal Transduction Skeleton Structure Structure-Activity Relationship System Tissues Transgenes Work base cell behavior cell motility comparative craniofacial craniofacial complex craniofacial development cranium developmental disease embryonic stem cell extracellular genetic approach insight meningioma migration mutant novel null mutation orofacial cleft population based prevent research study response skeletal skull base stem cell population

项目摘要

DESCRIPTION (provided by applicant): Embryonic development of craniofacial structures requires a tightly orchestrated series of cellular and morphological events. These include regulation of cellular proliferation, growth, migration, and differentiation. The sensitivity of thse processes to perturbation is evident by the high incidence of human birth defects affecting the head and associated structures (~75% of all birth defects have a craniofacial component), most common of which is orofacial clefting (~1:600-1,000 live births). These defects will impart a significant decrease in quality of life on those afflicted and present a major economic burden associated with treatment. To better understand and ultimately prevent these disorders prenatally a precise understanding of genes controlling the aforementioned cellular processes during normal craniofacial development is required. To this end, through an ENU based mutagenesis screen, we have identified Mediator of ErbB2-driven cell motility 1 (Memo1) as a novel regulator of multiple aspects of craniofacial development, including appropriate formation of the skull-base and palate. Interestingly, most of the affected structures in Memo1enu/enu mutants are derived from the cranial neural crest cells, implicating a role for Memo1 within this embryonic stem-cell population. Previous studies identified Memo1 as an important component in modulating extracellular cues into intracellular responses, such as cellular migration and proliferation. However, Memo1-null embryos are early embryonic lethal, precluding any analysis of Memo1's role during craniofacial development. Our Memo1 ENU-allele thus provides a unique model to decipher Memo1's role during these processes. Our general goal is to precisely characterize the mechanistic role of Memo1 during craniofacial development using two Aims. (AIM 1) First, by combining our Memo1 ENU-allele with a Memo1 null-allele, we will generate an allelic series, serving as a convenient genetic model system to dissect Memo1's cellular role during craniofacial development. The resultant allelic combinations will be utilized for analysis o gross craniofacial development and cranial neural crest cell biology, including a more detailed in vitro examination of neural crest cell migration. (AIM 2) Secondly, because Memo1 is expressed in multiple craniofacial tissues, we will generate a conditional allele of Memo1 allowing its tissu specific deletion. Given the majority of the defects in our ENU- mutant are found in structures derived from the cranial neural crest cells, we will specifically assess the cell autonomous requirements of Memo1 in this tissue by generating mutants with a neural crest specific deletion of Memo1, and thoroughly characterize how this impacts craniofacial development. In summary, Memo1 has only recently been linked with face formation but further characterization of this gene is likely to generate insight into the broader gene network responsible for normal human facial formation. In the long-term, the work proposed will contribute to a more detailed understanding of processes involved in craniofacial development, providing a clearer path towards detection and prevention of craniofacial disorders.

描述（由申请人提供）：颅面结构的胚胎发育需要一系列紧密协调的细胞和形态事件。这些包括细胞增殖、生长、迁移和分化的调节。这些过程对扰动的敏感性从影响头部和相关结构的人类出生缺陷的高发生率中可见一斑（约 75% 的出生缺陷有颅面部成分），其中最常见的是口面部裂（约 1:600- 1,000 名活产婴儿）。这些缺陷将显着降低患者的生活质量，并带来与治疗相关的重大经济负担。为了更好地了解并最终在产前预防这些疾病，需要精确了解在正常颅面发育过程中控制上述细胞过程的基因。为此，通过基于 ENU 的诱变筛选，我们确定了 ErbB2 驱动的细胞运动介体 1 (Memo1) 作为颅面发育多个方面的新型调节剂，包括颅底和腭的适当形成。有趣的是，Memo1enu/enu 突变体中大多数受影响的结构都源自颅神经嵴细胞，这表明 Memo1 在该胚胎干细胞群中发挥着作用。先前的研究发现 Memo1 是调节细胞外信号到细胞内反应（例如细胞迁移和增殖）的重要组成部分。然而，Memo1缺失的胚胎是早期胚胎致死的，因此无法对Memo1在颅面发育过程中的作用进行任何分析。因此，我们的 Memo1 ENU 等位基因提供了一个独特的模型来破译 Memo1 在这些过程中的作用。我们的总体目标是使用两个目标精确表征 Memo1 在颅面发育过程中的机械作用。 (AIM 1) 首先，通过将我们的 Memo1 ENU 等位基因与 Memo1 无效等位基因相结合，我们将生成一个等位基因系列，作为一个方便的遗传模型系统来剖析 Memo1 在颅面发育过程中的细胞作用。由此产生的等位基因组合将用于分析大体颅面发育和颅神经嵴细胞生物学，包括更详细的神经嵴细胞迁移的体外检查。 (AIM 2) 其次，由于 Memo1 在多个颅面组织中表达，我们将生成 Memo1 的条件等位基因，允许其组织特异性删除。鉴于我们的 ENU 突变体中的大部分缺陷都存在于源自颅神经嵴细胞的结构中，我们将通过生成具有神经嵴特异性删除 Memo1 的突变体来专门评估该组织中 Memo1 的细胞自主需求，并彻底评估 Memo1 的细胞自主需求。描述这如何影响颅面发育。总之，Memo1 最近才与面部形成联系起来，但对该基因的进一步表征可能会深入了解负责正常人类面部形成的更广泛的基因网络。从长远来看，拟议的工作将有助于更详细地了解颅面发育过程，为颅面疾病的检测和预防提供更清晰的途径。