The Dact1 mouse as a model for OEIS

Dact1 小鼠作为 OEIS 的模型

• 批准号: 7840373
• 负责人: Benjamin N.R. Cheyette
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/7840373
• 关键词: Affect; Animal Model; Animals; Anus; Birth; Bladder; Cell Death; Cessation of life; Collection; Color; Complex; Congenital Abnormality; Defect; Deterioration; Development; Distal; Dysmorphology; Embryo; Endoderm; Endoderm Cell; Etiology; FOLH1 gene; Failure; Fetus; Gastrointestinal tract structure; Genes; Genetic; Genetic Models; Genitalia; Genitourinary system; Hindgut; Human; Immigration; 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; infant death; malformation; migration; mutant; neonate; pleiotropism; protein function; selective expression; somitogenesis; spine bone structure; stillbirth

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（由申请方提供）：OEIS综合征是一种主要影响膀胱、远端消化道和脊椎骨骼的人类胎儿和婴儿畸形相关疾病。它和更广泛的畸形称为“下中胚层缺陷序列”，包括死产，围产期致死性和可矫正的出生缺陷的相对常见的偶发原因。目前对这些畸形的遗传或发育病因学知之甚少。本申请将使用细胞质信号调节剂Dact1中的靶向突变作为OEIS和相关畸形的动物模型。Dact1突变动物在出生前或出生后不久死于脐下腹壁、远端泌尿生殖系统、肛门和尾椎的联合缺陷。Dact1在胚胎早期在中胚层组织中表达。我假设Dact1蛋白的功能下游的WntSa和WntSa细胞间信号传导影响中胚层发育，这其次影响内胚层必要的膀胱，生殖器和肛门的形成。这一假说为OEIS和下中胚层缺陷序列提供了一个单一的遗传模型。我们将通过使用在我的实验室中创建的组成型和中胚层特异性Dact1突变小鼠品系，结合改变和监测Wnt信号的其他小鼠品系来测试这一假设。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，和（3）使用Dact1突变体作为中胚层加后肠衍生物缺陷的模型。研究设计利用了实验室小鼠中大量的遗传、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复杂的尾部畸形。这项研究对公共卫生很重要，因为它创造、建立和使用了一种新的动物模型来调查人类一系列复杂出生缺陷的起源。我们对Dact 1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胎、婴儿死亡和新生儿手术有显著影响。