Pitx2 and Wnt/PCP signaling in left-right asymmetric gut morphogenesis

Pitx2 和 Wnt/PCP 信号在左右不对称肠道形态发生中的作用

• 批准号: 8484834
• 负责人: Nanette M Nascone-Yoder
• 金额: $ 30.34万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484834
• 关键词: Address; Adhesions; Anatomy; Architecture; Automobile Driving; Cell Polarity; Cell Shape; Characteristics; Congenital Abnormality; DNA Sequence Rearrangement; Data; Development; Embryo; Endoderm; Endoderm Cell; Epithelial; Epithelium; Etiology; Event; Figs - dietary; Gastrocoele; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Homeostasis; Human; Individual; Intestines; Knowledge; Left; Life; Link; MAPK8 gene; Mediating; Mesenchymal; Modeling; Molecular; Morphogenesis; Organ; Pathway interactions; Pattern; Physiological; Play; Process; Radial; Reagent; Research; Rho-associated kinase; Role; Rotation; Side; Signal Transduction; Staging; Tissues; Tube; Work; Xenopus; Xenopus laevis; fascinate; gain of function; insight; intercalation; molecular asymmetry; novel; polarized cell; public health relevance; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): The vertebrate digestive tract develops left-right asymmetric loops and chiral rotations that are essential for normal physiological function. Perturbations of these fascinating anatomical features underlie the development of life-threatening congenital defects. In the early embryo, the initial determination of "left" versus "right" is manifest as unique left-right asymmetric gene expression patterns, including the left-limited expression of the transcription factor, Pitx2, which is required for normal asymmetric organ morphogenesis. However, the mechanism by which this molecular asymmetry then engenders morphological asymmetries within developing organs remains poorly understood. Preliminary data indicate that the endoderm cell rearrangements that drive tissue elongation and epithelial morphogenesis in the Xenopus primitive gut tube (PGT) are governed by Wnt/Planar Cell Polarity (Wnt/PCP) signaling, and are modulated by Pitx2 expression. The objective of this proposal is to determine the individual and combined roles of Pitx2 and Wnt/PCP signaling in regulating endoderm cell shape, adhesion and/or rearrangement during the development of left-right asymmetric anatomy in the digestive tract. Loss- and gain-of-function strategies will be employed, including the use of novel photoactivatable reagents that have been developed for side-, stage-, and tissue-specific spatiotemporal modulation of Wnt-PCP and Pitx2 expression in the Xenopus gut tube. Specific Aim 1 is to determine whether Wnt-PCP signaling regulates cell shape, adhesion and rearrangement in the endoderm during gut morphogenesis. Aim 2 is to determine whether asymmetric Pitx2 expression controls these parameters on the left side of the gut tube. Aim 3 is to determine whether the function of Pitx2 in asymmetric gut morphogenesis is mediated by Wnt-PCP signaling. Successful completion of the proposed research will provide unique insight into the unsolved mechanisms of asymmetric organ morphogenesis, by linking left-right asymmetric gene expression patterns to key mechanisms of asymmetric organ development.

描述（由申请人提供）：脊椎动物消化道形成左右不对称环和手性旋转，这对于正常生理功能至关重要。这些令人着迷的解剖学特征的扰动是危及生命的先天性缺陷的发展的基础。在早期胚胎中，“左”与“右”的最初确定表现为独特的左右不对称基因表达模式，包括转录因子 Pitx2 的左侧有限表达，这是正常不对称器官形态发生所必需的。然而，这种分子不对称导致发育器官内形态不对称的机制仍知之甚少。初步数据表明，非洲爪蟾原始肠管 (PGT) 中驱动组织伸长和上皮形态发生的内胚层细胞重排受 Wnt/平面细胞极性 (Wnt/PCP) 信号传导控制，并受 Pitx2 表达的调节。本提案的目的是确定 Pitx2 和 Wnt/PCP 信号在消化道左右不对称解剖发育过程中调节内胚层细胞形状、粘附和/或重排中的单独和组合作用。将采用功能丧失和获得的策略，包括使用新型光活化试剂，这些试剂已开发用于非洲爪蟾肠管中 Wnt-PCP 和 Pitx2 表达的侧面、阶段和组织特异性时空调节。具体目标 1 是确定 Wnt-PCP 信号传导是否调节肠道形态发生过程中内胚层的细胞形状、粘附和重排。目标 2 是确定不对称 Pitx2 表达是否控制肠管左侧的这些参数。目标 3 是确定 Pitx2 在不对称肠道形态发生中的功能是否由 Wnt-PCP 信号传导介导。通过将左右不对称基因表达模式与不对称器官发育的关键机制联系起来，拟议研究的成功完成将为不对称器官形态发生的未解决机制提供独特的见解。