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

在动物中，整个身体计划以及大多数器官和组织都是在胚胎发育期间形成的。Hox基因是一组核心的进化保守基因之一，这些基因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，这就提出了每个基因如何实现发育结果特异性的问题，以及它们的分子靶标在多大程度上依赖于细胞环境或在不同环境中共享。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。这项工作的科学目标和教育目标是交织在一起的。这项研究将与巴纳德学院的本科生合作进行，巴纳德学院是一所女子文理学院，包括实验室课程的学生，以及拉瓦尔大学的研究生。基于课程的研究已被证明可以增加本科生（包括那些来自代表性不足群体的学生）对STEM的参与，并增加对STEM研究生培训的追求。本课程让本科生从事实质性的原创性研究，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。Hoxa5是一个很好的模型，用于解决HOX上下文依赖性问题，这是由于不同组织和器官系统中的几种非冗余表型，以及大量可用的遗传工具。我们假设Hoxa5既调节环境依赖性的效应，也调节跨组织的共有效应。在这里，我们将研究与PDGF信号成分相互作用的共同作用，在不同的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肤组织谱系发展中的作用。最后，我们将使用无偏全基因组方法直接比较Hoxa5靶基因和不同组织类型的遗传途径。这项工作充分利用了Mansfield和Jeannotte实验室在肌肉骨骼和呼吸系统方面建立的合作、共同利益和综合专业知识。Hoxa5模型的结果将普遍适用于理解Hox基因在脊椎动物发育中的功能。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.