Leveraging the biphasic life cycle of a non-vertebrate chordate to investigate developmental transitions and phenotypic plasticity

PROJECT SUMMARY/ABSTRACT Our laboratory’s research on Ciona is centered on uncovering fundamental but currently unknown mechanisms regulating important cellular processes like fusion, survival, quiescence, and growth. Tunicates like Ciona are the invertebrates most closely related to vertebrates, yet possess a biphasic life cycle. During metamorphosis, a mass wave of cell death and resorption eliminates most differentiated larval cells while sparing set-aside undifferentiated adult progenitor cells that go on to form the majority of adult cell types and structures. In many cases, these adult cell types are distinct from their larval counterparts. For instance, while larval muscles are mononucleated, like that of other non-vertebrate deuterostomes, their adult muscles are multinucleated and form through myoblast fusion through the fusogenic factor Myomaker, which is shared only with vertebrates. We are particularly interested in understanding how these two very distinct muscle types (larval mononucleated vs. adult multinucleated) are made, and we hope to leverage this unique dichotomy to identify potentially conserved, but as-of-yet unidentified effectors of cell-cell fusion acting in the same Myomaker-dependent pathway. Our goal in the next 5 years for this specific project is to identify additional genes regulating cell-cell fusion and further our understanding, currently quite poor, of Myomaker structure-function at a subcellular level. Despite the heterochrony and phenotypic plasticity of larval vs. adult cells, and the complete remodeling of body plans and tissues, the larval and adult compartments are contiguous and simultaneously patterned during embryonic development. This peculiar arrangement offers a unique opportunity to study how discrete stem cell compartments can be set aside and protected for later developmental potential in spite of the differentiation and cell death around them. Our research has recently pinpointed the FGF/MAPK pathway as a key regulator of the fate choice between larval vs. adult cell. In the “Neck”, a compartment of the larval central nervous system, sustained FGF/MAPK signaling carves out a niche of adult-specific stem cells that survive metamorphosis and go on to proliferate and differentiate in the adult phase. By perturbing FGF/MAPK signaling, we can instead convert these cells into larval neurons, which are the fated to be eliminated during metamorphosis. In the next 5 years, our goal is to identify the pathways and molecular components downstream of FGF/MAPK that effect this dramatic death-or-survival switch.