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Mechanisms of Eph/Ephrin signaling in craniofacial morphogenesis and craniofrontonasal syndrome

Eph/Ephrin 信号在颅面形态发生和颅额鼻综合征中的机制

基本信息

批准号：
10165687
负责人：
Jeffrey Ohmann Bush
金额：
$ 49.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-09 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165687
关键词：
Actomyosin Affect Anterior Binding Candidate Disease Gene Cell Density Cell Polarity Cell Separation Cell Shape Cells Chest Cleft Palate Clustered Regularly Interspaced Short Palindromic Repeats Corpus Callosum Craniofacial Abnormalities Craniosynostosis Data Development Disease Dysmorphology Embryo Eph Family Receptors Ephrin B Receptor Ephrin Receptor EphB1 Ephrin-B1 Ephrins Exhibits Face Female Foundations Future Genes Genetic Goals Grant Heterozygote Histologic Human Individual Knowledge Label Lateral Limb structure Link Live Birth Mediator of activation protein Mesenchymal Mesenchyme Methods Modeling Molecular Morphogenesis Mosaicism Mus Mutation Neural Crest Cell Neurologic Nose Nuclear Orbital separation excessive Pathogenesis Pathologic Pathology Pattern Phase Phenotype Phosphotransferases Play Population Positioning Attribute Process Publishing Receptor Protein-Tyrosine Kinases Rho-associated kinase Role Scanning Secondary Palate Severities Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Skeleton Sorting - Cell Movement Structure System Technology Telencephalon Testing Therapeutic Tissues To specify Work X Inactivation base cell behavior cell motility cell type congenital anomaly craniofacial craniofacial development craniofacial tissue craniofrontonasal syndrome density design disease-causing mutation genetic approach genome editing improved induced pluripotent stem cell insight male microCT midfacial hypoplasia molecular scale mouse genetics mutant neural plate palatal shelves personalized medicine receptor segregation skeletal tool

项目摘要

Project summary Congenital anomalies affect 1% of live births, with one-third of these displaying craniofacial abnormalities. Great advances have been made in our understanding of the genetic causes of many of these conditions, but lack of understanding of the underlying developmental, cellular, and molecular mechanisms continues to stymie personalized medicine approaches to treat these conditions. Craniofrontonasal syndrome (CFNS) is an X-linked condition caused by mutations in the EFNB1 gene that affects craniofacial and thoracic skeleton, and neurological development. Complete loss of EFNB1 function results in hypertelorism and cleft palate, but mosaic loss of EFNB1 in only some cells, has more severe consequences, resulting also in midfacial hypoplasia, coronal craniosynostosis, limb abnormalities, and agenesis of the corpus callosum. Mouse Efnb1 mutants effectively model CFNS, exhibiting most of the same phenotypes. Efnb1 encodes Ephrin-B1 a transmembrane signaling molecule that binds to EphB receptor tyrosine kinases to regulate cell position. In Efnb1+/- heterozygous females, X chromosome inactivation leads to mosaicism for Ephrin-B1 function and subsequent sorting-out of Ephrin-B1-expressing cells from Ephrin-B1 mutant cells. This self-organizing capacity is a general feature of Eph/Ephrin signaling in many different tissues. In craniofacial development, we hypothesize that Ephrin-B1 plays a critical role in the organization of the craniofacial mesenchyme, though how this occurs, and how it affects craniofacial shape, remains unknown. It is therefore our goal to understand how Ephrin-B1 regulates normal craniofacial morphogenesis at the developmental, cellular and molecular scales. First, to understand how Ephrin-B1 regulates changes in shape of specific craniofacial embryonic primordia, we will utilize micro-computed tomography scanning to perform landmark-based morphometric analysis of mouse embryos lacking Ephrin-B1 in specific structures. Using a similar approach, we will evaluate the relative involvement of three receptors EphB1, EphB2 and EphB3 in craniofacial morphogenesis. Second, we will utilize new tools to study the distribution, shape, density, and polarity of the craniofacial mesenchyme in normal and Efnb1 mutant embryos. Finally, we will harness CRISPR genome editing technology to perform a functional screen of candidate genes to identify the signaling pathways downstream of Ephrin-B1/EphB signaling. This work will provide new insights into the mechanisms by which Ephrin-B1 normally controls mesenchymal cell behaviors in craniofacial morphogenesis, and determine how its loss results in pathological changes in craniofacial shape. These studies will therefore provide foundational knowledge toward our long- term goal of developing improved therapies for the treatment of individuals with craniofacial anomalies and an improved understanding of the fundamental processes of craniofacial morphogenesis. The underlying cellular and molecular mechanisms may also be relevant to any of the numerous contexts where Eph/Ephrin signaling is important in development and disease.

项目摘要先天性畸形影响1%的活产婴儿，其中三分之一显示颅面畸形。我们对许多这些疾病的遗传原因的理解已经取得了很大的进步，但是对潜在的发育、细胞和分子机制缺乏了解，阻碍了个性化医疗方法来治疗这些疾病。颅额鼻综合征（CFNS）是一种由影响颅面和胸部骨骼的EFNB 1基因突变引起的X连锁疾病，以及神经发育EFNB 1功能的完全丧失会导致距离过远和腭裂，但仅在一些细胞中的EFNB 1镶嵌性丢失，具有更严重的后果，也导致面中部发育不全、冠状颅缝早闭、肢体畸形和胼胝体发育不全。小鼠Efnb 1 突变体有效地模拟CFNS，表现出大多数相同的表型。Efnb 1编码Ephrin-B1 a EphB是一种跨膜信号分子，与EphB受体酪氨酸激酶结合以调节细胞位置。在 Efnb 1 +/-杂合子女性，X染色体失活导致Ephrin-B1功能嵌合，随后从Ephrin-B1突变细胞中分选出Ephrin-B1表达细胞。这种自我组织容量是许多不同组织中Eph/Ephrin信号传导的一般特征。在颅面发育中，我们假设Ephrin-B1在颅面间充质的组织中起着关键作用，尽管如何这种情况的发生，以及它如何影响颅面形状，仍然是未知的。因此，我们的目标是了解 Ephrin-B1在发育、细胞和分子水平上调节正常颅面形态发生。首先，为了了解Ephrin-B1如何调节特定颅面胚胎原基形状的变化，我们将利用微计算机断层扫描进行基于地标的形态测量分析，在特定结构中缺乏Ephrin-B1的小鼠胚胎。使用类似的方法，我们将评估相对三种受体EphB 1、EphB 2和EphB 3参与颅面形态发生。二是利用新的工具来研究正常颅面间充质的分布、形状、密度和极性，和Efnb 1突变胚胎。最后，我们将利用CRISPR基因组编辑技术进行候选基因的功能筛选以鉴定Ephrin-B1/EphB下游的信号通路信号这项工作将提供新的见解的机制，其中Ephrin-B1通常控制间充质细胞的行为在颅面形态发生，并确定其损失如何导致病理性颅面形状的改变。因此，这些研究将为我们长期的研究提供基础知识。长期目标是开发用于治疗颅面畸形和提高对颅面形态发生基本过程的理解。潜在的细胞并且分子机制也可能与Eph/Ephrin信号传导对发育和疾病都很重要。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate.

DOI：
10.1002/dvdy.24170
发表时间：
2014-11
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Agrawal P;Wang M;Kim S;Lewis AE;Bush JO
通讯作者：
Bush JO

Investigating the effects of compound paralogous EPHB receptor mutations on mouse facial development.

研究复合寄生虫EPHB受体突变对小鼠面部发育的影响。