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

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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.