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）：脊椎动物消化道会形成对正常生理功能必不可少的左右不对称环和手性旋转。这些迷人的解剖学特征的扰动是威胁生命的先天性缺陷的发展。在早期的胚胎中，“左”与“右”的初始确定表现为独特的左右不对称基因表达模式，包括转录因子的左限制表达PITX2，这是正常不对称器官形态发生所必需的。然而，这种分子不对称的机制随后导致了发育中的器官内部的形态不对称性。初步数据表明，在异爪蟾原始肠道管（PGT）中驱动组织伸长和上皮形态发生的内胚层重排受到WNT/Planar Cell Pallity（Wnt/PCP）信号的控制，并且由PITX2表达进行了调节。该提案的目的是确定pitx2和Wnt/pcp信号在调节内胚层细胞形状，粘附和/或重排期间的个体和联合作用，在消化道中左右不对称解剖结构的发展过程中。将采用损失和功能收益策略，包括使用新型的光活化试剂，这些试剂用于在爪蟾肠道管中用于Wnt-PCP和PITX2表达的侧，阶段和组织特异性时空调制。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中的细胞形状，粘附和重排。 AIM 2是确定不对称的PITX2表达是否控制着肠管左侧的这些参数。 AIM 3是确定PITX2在不对称肠道形态发生中的功能是否是由Wnt-PCP信号传导介导的。成功完成拟议的研究将通过将左右右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，从而为未解决的不对称器官形态发生的未解决机制提供独特的见解。