Sunday, May 18, 2025
5/18/2025
The Evolution of Sexually Dimorphic Morphogenesis - PROJECT SUMMARY/ABSTRACT Although the processes that regulate sexual dimorphism vary between taxa, a group of genes known as DM domain transcription factors (DMRT TFs) play a major role in the development of male-specific traits. How these TFs are linked to morphogenetic effectors, however, is unknown. Also, it is unclear what parts of morphogenetic regulation and its machinery are evolutionarily constrained versus plastic. Here, 4 tail tip cells of Caenorhabditis elegans are used as a model system to address these knowledge gaps. During the last larval stage (L4), in males only, these cells undergo Tail Tip Morphogenesis (TTM). The DMRT TF, DMD-3, is required and sufficient for TTM. A paralog, MAB-3, also regulates TTM in a role not well understood. Also, TTM has evolved repeatedly in nematodes, providing an opportunity to determine how conserved or evolvable is TTM and its transcriptional regulation. The overall goal is to delineate what genes are transcriptionally controlled by DMD-3 and MAB-3, to determine the extent of overlap in targets between these TFs, and to determine what parts of this transcriptional control are constrained vs. plastic via interspecific comparisons. Aim 1 is to delineate how DMD-3 transcriptionally controls TTM and how MAB-3 contributes to this regulation (i.e. how much of MAB-3 contribution is due to overlapping vs. non-overlapping control). This will be done by comparing transcriptome profiles of single tail tips throughout TTM from wild-type males to those from DMD-3 and MAB-3 mutants. Direct vs. indirect targets of DMD-3 will be distinguished by comparing these data to whole-worm DMD-3 ChIP-seq data previously obtained in the lab. Aim 2 is to determine how plastic or constrained is the regulation of TTM across different nematode species by using the same tail-tip-specific RNA-seq approach on species in which TTM repeatedly evolved, and will identify which parts of the transcriptome are conserved. The expected outcome is an understanding of how transcriptional regulation by DMD-3 and MAB-3 is linked to morphogenetic effectors, what is the role of MAB-3, and what parts of the transcriptional regulation are conserved versus evolvable. These results are expected to have a positive impact on medicine, as they could identify key conserved genes that control particular aspects of morphogenesis as in birth defects or cancer. Goals of the integrated training plan are to deepen knowledge, gain skills in rigorous experimental design, hone communication skills, augment leadership and mentoring skills, and transition toward an independent career in biomedical research. This training will be carried out using the above research as a platform for one-on-one mentoring, as well as coursework, journal clubs, seminars, an advisory committee, teaching experience, conferences, retention mechanisms and many other resources. This training will occur in a nurturing, collaborative environment with state-of-the-art facilities and equipment, high-quality NIH-supported curricula in developmental systems biology, and a proven record of producing diverse, top-notch scientists.
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