The Dact1 mouse as a model for OEIS

Dact1 小鼠作为 OEIS 的模型

基本信息

批准号：
8076837
负责人：
Benjamin N.R. Cheyette
金额：
$ 31.66万
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：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8076837
关键词：
Affect Animal Model Animals Anus Birth Bladder Cell Death Classification Collection Complex Congenital Abnormality Congenital omphalocele Defect Deterioration Development Developmental Biology Distal Embryo Endoderm Endoderm Cell Epithelium Etiology FOLH1 gene Failure Fetus Gastrointestinal tract structure Genes Genetic Genetic Models Genitalia Genitourinary system Hindgut Human Immigration Laboratories Laboratory mice Lead Ligands Mesoderm Mesoderm Cell Modeling Molecular Genetics Monitor Morphogenesis Morphology Mus Mutant Strains Mice Mutate Mutation Neonatal Online Mendelian Inheritance In Man Operative Surgical Procedures Perinatal Phenocopy Phenotype Primitive Streaks Process Production Public Health Relative (related person)Research Research Design Resources Role Series Signal Pathway Signal Transduction Skeleton Somites Spinal Syndrome Tail Testing Tissues Transcriptional Activation United States Vertebral column abdominal wall base cell motility early embryonic stage infant death malformation migration mutant neonate progenitor protein function selective expression somitogenesis spine bone structure stillbirth

项目摘要

DESCRIPTION (provided by applicant): The OEIS complex is an association of malformations in human fetuses and babies primarily affecting the bladder, distal digestive tract, and vertebral skeleton. It and a broader spectrum of malformations called the 'lower mesodermal defects sequence," comprise a relatively common sporadic cause of stillbirth, perinatal lethality, and surgically-correctable birth defects. Very little is currently understood about the genetic or developmental etiology of this collection of malformations. This application will use a targeted mutation in the cytoplasmic signaling modulator Dact1 as an animal model for OEIS and related malformations. Dact1 mutant animals die shortly before or after birth from combined defects in the infraumbilical abdominal wall, the distal urogenital system, the anus, and the caudal vertebral column. Dact1 is expressed at early embryonic stages in mesodermal tissues. I hypothesize that the Dact1 protein functions downstream of both WntSa and WntSa intercellular signaling to influence mesoderm development, and that this secondarily affects the endoderm necessary for formation of the bladder, genitalia, and anus. This hypothesis provides a single hit genetic model for OEIS and the lower mesodermal defects sequence. We will test this hypothesis by making use of constitutive and mesoderm-specific Dact1 mutant mouse lines created in my laboratory, in combination with other mouse lines that alter and monitor Wnt signaling. The specific aims are: (1) To determine the role of Dact1 in Wnt5a-dependent signaling and mesoderm proliferation, migration and survival, (2) To determine the role of Dact1 in WntSa-dependent signaling and mesoderm differentiation, and (3) To use Dact1 mutants as a model for defects in mesodermal plus hindgut derivatives. The research design draws on the tremendous genetic, molecular, and embryonic experimental resources available in the laboratory mouse. It will probe contributions of the Dact1 gene to mesoderm and endoderm development, the signaling pathways involved, and how disruptions in Dact1 function lead to complex caudal malformations in neonates.

描述（由申请人提供）：OEIS综合体是人类胎儿和婴儿中主要影响膀胱，远端消化道和椎骨骨骼的畸形缔合。 IT和更广泛的畸形称为“下胚层缺陷序列”，构成了相对常见的零星原因，导致了死产，围产致死性和手术性先天性缺陷。畸形。和尾椎骨。膀胱，生殖器和肛门。该假设为OEI和下胚层缺损提供了单个遗传模型。我们将通过利用在我的实验室中创建的组成型和中胚层特异性DACT1突变型小鼠系，结合其他改变和监视Wnt信号传导的小鼠线结合使用来检验这一假设。具体目的是：（1）确定DACT1在Wnt5a依赖性信号传导和中胚层增殖，迁移和存活中的作用，（2）确定DACT1在WNTSA依赖性信号传导和中胚层分化中的作用，以及（3）使用DACT1突变体作为中胚层和后肠衍生物缺陷的模型。研究设计借鉴了实验室小鼠中可用的巨大遗传，分子和胚胎实验资源。它将探测DACT1基因对中胚层和内胚层发育的贡献，所涉及的信号通路以及DACT1功能的破坏如何导致新生儿的复杂尾畸形。