Ahead of the Curve: Mechanisms of Left-Right Asymmetric Stomach Morphogenesis

引领潮流：左右不对称胃形态发生的机制

基本信息

批准号：
10397529
负责人：
Nanette M Nascone-Yoder
金额：
$ 30.23万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397529
关键词：
Address Adopted Amphibia Anatomy Animal Model Behavior Bilateral Biological Biological Assay Candidate Disease Gene Cell physiology Cells Clinical Complement Complex Congenital Abnormality Cues Data Data Set Defect Development Digestive Physiology Dissection Economic Burden Embryo Etiology Event Family Gene Expression Genes Genetic Goals Handedness Individual Infant Mortality Knowledge Left Life Logic Mammals Manuals Modeling Molecular Molecular Profiling Morphogenesis Nodal Organ Organogenesis Pathway interactions Pattern Phase Phenotype Positioning Attribute Process Property Radial Rana Regulator Genes Research Shapes Side Situs Inversus Stomach Structural Congenital Anomalies Testing Thinness Tissues Tube United States Vertebrates Xenopus body system driving force gain of function gene discovery gene regulatory network innovation insight malformation novel programs spatiotemporal transcriptome transcriptome sequencing validation studies

项目摘要

Project Summary Birth defects are a leading cause of infant mortality, yet in most cases, their etiology is unknown. Some of the most common and complex malformations are found in families with abnormal left-right (LR) asymmetry, suggesting that many congenital defects may result from perturbed laterality. The initial embryonic events that determine the LR body axis, including the early breaking of bilateral symmetry, and subsequent left-sided expression of determinants such as nodal and Pitx2, are now well understood. However, the genetic and morphogenetic events involved in the final phases of LR development, at the organ level, remain largely unknown. The long term goal is to ascertain the mechanisms of LR asymmetric organogenesis. The objective in this application is to identify the molecular and cellular processes that generate LR asymmetry (curvature) within an individual organ, the stomach. Preliminary analyses identified LR asymmetries in radial cell rearrangements in the developing stomach as the driving force for its curvature. To identify the proximate effectors of this novel asymmetric morphogenetic program, a new model organism (Lepidobatrachus laevis) was employed. The extra-large embryos of this species facilitated a gene-discovery approach that would be intractable in most models: transcriptome profiling (RNASeq) of tissues dissected from left vs. right halves of the embryonic stomach. Pilot datasets include genes with LR asymmetric expression patterns and functions during stomach curvature. The central hypothesis is that stomach curvature is determined by distinct left and right regulatory networks which differentially modulate the cellular events controlling radial cell rearrangement. The unique experimental amenability of frog embryos will be used to test this hypothesis via three specific aims: 1) Generate molecular signatures of normal and abnormal stomach curvature. Comprehensive spatiotemporal profiles of LR stomach genes will be generated and compared in the context of both normal LR asymmetry and experimentally-induced LR axis defects. 2) Determine the cellular function of stomach- specific LR genes. Select genes will be tested in loss- and gain-of-function assays to determine their influence on radial cell rearrangement in the developing stomach. 3) Determine the regulatory hierarchy that controls stomach curvature. Experimental perturbations combined with spatiotemporal profiling will reveal core gene regulatory interactions governing asymmetric morphogenesis. The overall approach is innovative because it takes advantage of distinctive attributes of a unique species to address one of the key unanswered questions in LR development: what are the proximate mechanisms by which developing organs become LR asymmetric entities? The proposed research is significant because it will immediately advance our understanding of normal laterality and laterality-related birth defects by defining the genes, morphogenetic processes and regulatory logic that govern the emergence of LR asymmetry at the organ level.

项目概要出生缺陷是婴儿死亡的主要原因，但在大多数情况下，其病因尚不清楚。一些最常见和最复杂的畸形出现在左右不对称（LR）异常的家族中，表明许多先天性缺陷可能是由偏侧性扰动造成的。最初的胚胎事件确定 LR 体轴，包括双侧对称性的早期破坏以及随后的左侧对称性诸如 nodal 和 Pitx2 等决定因素的表达现在已得到很好的理解。然而，遗传和在器官水平上，参与 LR 发育最后阶段的形态发生事件在很大程度上仍然存在未知。长期目标是确定 LR 不对称器官发生的机制。目标此应用程序的目的是识别产生 LR 不对称性（曲率）的分子和细胞过程在一个单独的器官内，胃。初步分析发现径向细胞中存在 LR 不对称性发育中胃的重新排列作为其弯曲的驱动力。来识别最接近的这种新颖的不对称形态发生程序的效应器，一种新的模式生物（Lepidobatrachus laevis）被雇用了。该物种的超大胚胎促进了基因发现方法在大多数模型中都难以解决：从左半部和右半部解剖的组织的转录组分析（RNASeq）胚胎胃。试点数据集包括具有 LR 不对称表达模式和功能的基因胃弯曲时。中心假设是胃曲率是由不同的左、右胃曲率决定的。正确的调节网络可以差异性地调节控制径向细胞重排的细胞事件。青蛙胚胎独特的实验适应性将用于通过三个特定的方法来检验这一假设目标：1) 生成正常和异常胃曲率的分子特征。综合的将生成 LR 胃基因的时空图谱，并在正常情况下进行比较 LR 不对称和实验引起的 LR 轴缺陷。 2) 确定胃的细胞功能- 特定的LR基因。选定的基因将在功能丧失和获得功能测定中进行测试，以确定其对发育中的胃中径向细胞重排的影响。 3）确定监管层级控制胃的曲度。实验扰动与时空分析相结合揭示控制不对称形态发生的核心基因调控相互作用。总体方法是创新是因为它利用独特物种的独特属性来解决关键问题之一 LR 发育中尚未解答的问题：发育器官的直接机制是什么？成为LR非对称实体？拟议的研究意义重大，因为它将立即推进通过定义基因、形态发生，我们对正常偏侧性和偏侧性相关出生缺陷的理解控制器官水平 LR 不对称性出现的过程和调节逻辑。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Morphoelastic models discriminate between different mechanisms of left-right asymmetric stomach morphogenesis.

形态弹性模型区分左右不对称胃形态发生的不同机制。

DOI：
10.1016/j.cdev.2024.203902
发表时间：
2024
期刊：
Cells & development
影响因子：
3.9
作者：
Nikas,ArielN;Curcio,EvanJ;Nascone-Yoder,Nanette;Lubkin,SharonR
通讯作者：
Lubkin,SharonR

The twists and turns of left-right asymmetric gut morphogenesis.

左右不对称肠道形态发生的曲折。

DOI：
10.1242/dev.187583
发表时间：
2020
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Grzymkowski,Julia;Wyatt,Brent;Nascone-Yoder,Nanette
通讯作者：
Nascone-Yoder,Nanette

Single-minded 2 is required for left-right asymmetric stomach morphogenesis.

左右不对称的胃形态发生需要“一心一意”2。

DOI：
10.1242/dev.199265
发表时间：
2021
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Wyatt,BrentH;Amin,NiravM;Bagley,Kristen;Wcisel,Dustin;Dush,MichaelK;Yoder,JeffreyA;Nascone-Yoder,NanetteM
通讯作者：
Nascone-Yoder,NanetteM

Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.

DOI：
10.1016/j.xhgg.2023.100232
发表时间：
2023-10-12
期刊：
HUMAN GENETICS AND GENOMICS ADVANCES
影响因子：
0
作者：
Blue, Elizabeth E.;White, Janson J.;Dush, Michael K.;Gordon, William W.;Wyatt, Brent H.;White, Peter;Marvin, Colby T.;Helle, Emmi;Ojala, Tiina;Priest, James R.;Jenkins, Mary M.;Almli, Lynn M.;Reefhuis, Jennita;Pangilinan, Faith;Brody, Lawrence C.;McBride, Kim L.;Garg, Vidu;Shaw, Gary M.;Romitti, Paul A.;Nembhard, Wendy N.;Browne, Marilyn L.;Werler, Martha M.;Kay, Denise M.;Mital, Seema;Chong, Jessica X.;Nascone-Yoder, Nanette M.;Bamshad, Michael J.
通讯作者：
Bamshad, Michael J.