Cellular morphogenesis is essential to animal development and growth as well as wound healing and cancer. During this process, cells coordinately change shape, migrate, and may fuse. Cellular morphogenesis is executed by molecules called effectors involved in junctions, cytoskeleton, cell polarity, vesicular trafficking, and other modules/processes of the cytological machinery. The sex-, tissue-, position-, and time- specificity of morphogenesis is determined by regulators, such as transcription factors. How transcription factors connect to and coordinate the cellular effectors to control morphogenesis is a major knowledge gap in the field. Here, the overall objective is to elucidate this connection for an experimentally accessible model structure, the tail tip of C. elegans. The tail tip is made of 4 cells which, in males only, radically alter their shape and position at the juvenile-to-adult transition, a process called Tail Tip Morphogenesis (TTM). Prior studies showed that the transcription factor DMD-3 is a master regulator (required and sufficient) for TTM and is predicted to coordinate several underlying modules/ processes of the cytological machinery. The overall approach is to determine what effectors are directly transcriptionally regulated by DMD-3 and to determine their respective functional roles in TTM, i.e. which cytological modules they affect.
Aim 1 is to identify the direct target genes of DMD-3 by ChIP-seq and validate at least some of them.
Aim 2 is to determine what roles at least a few DMD-3-controlled genes have in TTM by genetically perturbing them and using a toolkit of cellular markers to identify what cytological processes are governed by these effectors. The expected outcome is a network system model showing how transcriptional regulation is connected to?i.e. how it coordinates?the various parts of the cell machinery underylying TTM, thus addressing the major knowledge gap noted above. These results are expected to have a positive impact on medicine, as they could identify key conserved genes that control particular aspects of morphogenesis. Such genes could provide new targets for drugs to mitigate the effects of birth defects or cancer, or to aid wound healing. For the underrepresented minority predoctoral student responsible for carrying out all the research proposed above, the goals of the integrated training plan are to (1) deepen knowledge in the fields of molecular, cell and developmental biology, (2) gain skills in ethically and scientifically rigorous experimental design and execution, (3) hone oral and written communication skills, (4) augment leadership and mentoring skills, and (5) 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, 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.
Morphogenesis is a universally important process in growth and development that involves changes in cell shape and position that must occur in the correct sex at precisely the right time and place, yet a comprehensive understanding of how gene expression controls the cellular machinery underlying morphogenesis is still lacking. Here, Mr. Porfirio Fernandez will undergo training for a biomedical research career and perform research to determine how a transcription factor, DMD-3, controls effectors of the sex- specific, postembryonic morphogenesis of the four-celled tail tip in C. elegans males. This study will lead to a model for how genes interact to produce biological form, thus providing a basis to identify key conserved components that control morphogenesis and which could therefore provide new targets for pharmaceuticals or other interventions to aid wound healing or to mitigate the effects of morphogenetic faults contributing to birth defects or cancer.
