The Dact1 mouse as a model for OEIS

Dact1 小鼠作为 OEIS 的模型

基本信息

批准号：
7240919
负责人：
Benjamin N.R. Cheyette
金额：
$ 33.86万
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/7240919
关键词：
Affect Animal Model Animals Anus Birth Bladder Cell Death Cessation of life Closure Collection Color Complex Congenital Abnormality Defect Deterioration Development Disruption Distal Dysmorphology Embryo Endoderm Endoderm Cell Etiology FOLH1 gene Failure Fetus Gastrointestinal tract structure Genes Genetic Genetic Models Genitalia Genitourinary system Hindgut Human Immigration Infant Laboratories Laboratory mice Lead Mesoderm Mesoderm Cell Modeling Molecular Genetics Monitor Morphogenesis Morphology Mus Mutant Strains Mice Mutation Neonatal Operative Surgical Procedures Organ Perinatal Phenotype Primitive Streaks Public Health Relative (related person)Research Research Design Research Personnel Resources Role Series Signal Pathway Signal Transduction Skeleton Tail Testing Text Tissue Survival Tissues United States Vertebral column abdominal wall base early embryonic stage malformation migration mutant neonate pleiotropism 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. This research is important to public health because it creates, establishes, and uses a new animal model to investigate the origins of a series of complex birth defects in humans. Our studies of the Dact1 mouse will help uncover the genetic, molecular, and cellular basis for birth defects that contribute significantly to still-births, infant deaths, and neonatal surgeries in the United States.

描述（由申请人提供）：OEIS 综合征是人类胎儿和婴儿畸形的一种关联，主要影响膀胱、远端消化道和椎骨。它和更广泛的畸形，称为“下中胚层缺陷序列”，构成了死产、围产期死亡率和可手术纠正的出生缺陷的相对常见的散发原因。目前，人们对这一系列畸形的遗传或发育病因知之甚少。该应用将使用细胞质信号调节剂 Dact1 中的靶向突变作为 OEIS 和相关畸形动物在出生前或出生后不久死亡的动物模型。脐下腹壁、远端泌尿生殖系统、肛门和尾椎的联合缺陷导致 Dact1 在胚胎早期的中胚层组织中表达，我推测 Dact1 蛋白在 WntSa 和 WntSa 细胞间信号传导的下游发挥作用。影响中胚层发育，进而影响膀胱、生殖器和肛门形成所必需的内胚层。该假设提供了单一打击遗传模型。用于 OEIS 和下中胚层缺陷序列。我们将利用我实验室创建的组成型和中胚层特异性 Dact1 突变小鼠系，并结合其他改变和监测 Wnt 信号传导的小鼠系，来检验这一假设。具体目标是：(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 突变体作为中胚层加后肠衍生物缺陷的模型。该研究设计利用了实验室小鼠中可用的大量遗传、分子和胚胎实验资源。它将探讨 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复杂的尾部畸形。这项研究对公共卫生很重要，因为它创建、建立和使用一种新的动物模型来研究人类一系列复杂出生缺陷的起源。我们对 Dact1 小鼠的研究将有助于揭示出生缺陷的遗传、分子和细胞基础，这些缺陷对美国的死产、婴儿死亡和新生儿手术有重大影响。