Collaborative Proposal: RUI: Understanding the context-dependent roles of HOXA5 in cell fate and patterning

合作提案：RUI：了解 HOXA5 在细胞命运和模式中的背景依赖性作用

• 批准号: 2019537
• 负责人: Jennifer Mansfield
• 金额: $ 86.28万
• 依托单位: Barnard College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2019537&HistoricalAwards=false
• 关键词: Collaborative; Proposal; RUI; Understanding; context

In animals, the overall body plan as well as most organs and tissues arise during embryonic development. The Hox genes are among a core set of evolutionarily conserved genes that activate and coordinate developmental processes such that each structure forms correctly, and in proper relation to the rest of the body. Hox genes are redeployed multiple times and in numerous tissues, raising the question of how specificity of developmental outcome is achieved for each gene, and the extent to which their molecular targets are dependent on cellular context or shared across contexts. This work will test this question using the Hoxa5 gene in the mouse model, by characterizing and comparing its molecular targets across selected musculoskeletal and respiratory tissues. The scientific and educational goals of this work are intertwined. The research will be conducted in collaboration with undergraduates at Barnard College, a liberal arts college for women, including students in a laboratory course, as well as graduate students from Université Laval. Course-based research has been shown to increase participation of undergraduate students, including those from underrepresented groups, in STEM and to increase the pursuit of postgraduate STEM training. This course engages undergraduates in substantive original research while providing them with training in current molecular genetics and bioinformatics approaches. Hoxa5 is an excellent model for addressing questions of HOX context-dependence due to several non-redundant phenotypes in different tissue and organ systems, and a wealth of genetic tools available. We hypothesize that Hoxa5 regulates both context-dependent and shared effectors across tissues. Here, we will examine a shared role in interaction with PDGF signaling components, producing distinct outcomes in different tissues. We will also assess the role of Hoxa5 in the development of dermomyotome lineages including skeletal muscle and brown adipose tissue. Finally, we will use unbiased whole-genome approaches to directly compare Hoxa5 target genes and genetic pathways across tissue types. The work leverages the established collaboration, shared interests and combined expertise of the Mansfield and Jeannotte labs in the musculoskeletal and respiratory systems. Results from the Hoxa5 model will apply generally to understanding Hox gene functions in vertebrate development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在动物中，整体身体结构以及大多数器官和组织是在胚胎发育过程中形成的。 Hox 基因是一组进化上保守的核心基因之一，它激活和协调发育过程，使每个结构正确形成，并与身体的其他部分保持适当的关系。 Hox 基因在许多组织中被多次重新部署，这就提出了一个问题：每个基因如何实现发育结果的特异性，以及它们的分子靶标在多大程度上依赖于细胞环境或跨环境共享。这项工作将通过在小鼠模型中使用 Hoxa5 基因来测试这个问题，通过表征和比较其在选定的肌肉骨骼和呼吸组织中的分子靶点。这项工作的科学和教育目标是相互交织的。该研究将与巴纳德学院（一所女子文理学院）的本科生合作进行，其中包括实验室课程的学生以及拉瓦尔大学的研究生。事实证明，基于课程的研究可以增加本科生（包括来自代表性不足群体的学生）对 STEM 的参与，并增加对研究生 STEM 培训的追求。本课程让本科生参与实质性的原创研究，同时为他们提供当前分子遗传学和生物信息学方法的培训。 由于不同组织和器官系统中存在多种非冗余表型，并且有大量可用的遗传工具，Hoxa5 是解决 HOX 上下文依赖性问题的出色模型。我们假设 Hoxa5 调节跨组织的上下文依赖性效应器和共享效应器。在这里，我们将研究与 PDGF 信号成分相互作用的共同作用，在不同组织中产生不同的结果。我们还将评估 Hoxa5 在包括骨骼肌和棕色脂肪组织在内的皮肌瘤谱系发育中的作用。最后，我们将使用无偏见的全基因组方法直接比较 Hoxa5 靶基因和跨组织类型的遗传途径。这项工作利用了曼斯菲尔德和让诺特实验室在肌肉骨骼和呼吸系统方面的既定合作、共同兴趣和综合专业知识。 Hoxa5 模型的结果将普遍适用于了解脊椎动物发育中的 Hox 基因功能。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Evolutionary assembly and disassembly of the mammalian sternum

哺乳动物胸骨的进化组装和拆卸

• DOI: 10.1016/j.cub.2022.11.055
• 发表时间: 2023
• 期刊: Current Biology
• 影响因子: 9.2
• 作者: Brent, Ava E.;Buchholtz, Emily A.;Mansfield, Jennifer H.
• 通讯作者: Mansfield, Jennifer H.