Mechanisms of physiological skin remodeling in African lungfish water-land transitions

Some animals can adapt and survive in extreme environments thanks to biological innovations. African lungfish are freshwater fish that can live as free swimming animals but also can survive on land for long periods of time when the dry season arrives. The process of adapting to live on land involves whole organism changes that are poorly understood. Specifically, this water-to-land movement requires the skin to undergo self-inflicted damage that ends in the formation of a protective cocoon. This proposal investigates the mechanisms by which African lungfish can transform its skin from a mucosal epithelium (water phase) to a terrestrial-like non mucosal epithelium (land phase). The goal of this proposal is to determine how a specific pore-forming toxin made in the African lungfish changes the cellular trajectory of the main cell type responsible for mucus secretion in the skin. Using African lungfish, as well as zebrafish genetic lines, the research will determine how this toxin impacts skin composition during normal conditions and under inflammatory conditions. The outcomes of this work will advance fundamental strategies that support skin remodeling in extreme environments and could result in biotechnological advances in skin regeneration and wound healing. Broader impacts also include new hands-on teaching materials to be delivered in middle schools in the Albuquerque metro area and free to download online as educational materials. Estivation and cocoon formation require a drastic remodeling process of the skin which in African lungfish is characterized by initial secretion of mucus, desquamation of keratinocytes and a global state of inflammation. Return to water results in the skin switching back to its free-swimming configuration. Preliminary studies identified a toxin, Protop-CrtxA, which is expressed by goblet cells in the lungfish skin and by granulocytes in internal reservoir organs at the steady state. Upon estivation, granulocytes migrate to the skin and secrete Protop-CrtxA. Our hypothesis is that in African lungfish the CrtXA toxin is a cell-intrinsic regulator of mucus secretion in goblet cells at the steady state and a cell-extrinsic switch for keratinocyte differentiation necessary for skin remodeling during water-land-water transitions. The goal of this proposal is to understand the physiological and molecular mechanisms by which African lungfish remodel their skin during water-land-water transitions. Specifically, this proposal aims to answer the following questions: (1) What are the cellular and molecular pathways supporting skin remodeling in African lungfish water-land-water transitions? ; (2) How does Protop-CrTXA regulate mucus production in goblet cells in a cell-intrinsic manner? ; and (3)What are the cell-extrinsic functions of Protop-CrtXA in keratinocyte differentiation? Combining in vivo estivation and return to water experiments, single cell RNA-Seq, new genetic models and in vivo and in vitro assays, we will determine the mechanisms by which African lungfish can remodel its skin in response to environmental changes. The outcomes of the proposed work will not only uncover fundamental physiological innovations in vertebrate mucosal barriers but also have the potential to translate into many future real-life biotechnological applications that benefit society. 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. NSF Award ID: 2546516 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Irene Salinas | Institution: University of New Mexico, ALBUQUERQUE, NM | Award Amount: $1,132,338 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2546516 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2546516.html