The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.
Abstract:Cardiovascular cell lineages emerge with kidney, smooth muscle, and limb skeleton progenitors from the lateral plate mesoderm (LPM). How the LPM emerges during development and how it has evolved to form key lineages of the vertebrate body plan remain unknown. Here, we captured LPM formation by transgenic in toto imaging and lineage tracing using the first pan-LPM enhancer element from the zebrafish gene draculin (drl). drl LPM enhancer-based reporters are specifically active in LPM-corresponding territories of several chordate species, uncovering a universal LPM-specific gene program. Distinct from other mesoderm, we identified EomesA, FoxH1, and MixL1 with BMP/Nodal-controlled Smad activity as minimally required factors to drive drl-marked LPM formation. Altogether, our work provides a developmental and mechanistic framework for LPM emergence and the in vitro differentiation of cardiovascular cell types. Our findings suggest that the LPM may represent an ancient cell fate domain that predates ancestral vertebrates.. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/261115 doi: bioRxiv preprint first posted online Feb. 7, 2018; 2 Main Text:Following gastrulation, mesoderm in vertebrates is classically described to partition into axial, paraxial, and lateral domains (Gurdon, 1995). The ventrally forming lateral plate mesoderm (LPM) is composed of highly mobile cells and is mainly defined by its position adjacent to the somite-forming paraxial mesoderm (Hatada and Stern, 1994). Transplantation and lineage tracing experiments in several species have shown that the LPM contains progenitor cells of the circulatory system, smooth muscle lineages, the kidneys (often demarcated as dedicated intermediate mesoderm), and the limb anlagen (Chal and Pourquié, 2017; Gurdon, 1995; Takasato and Little, 2015). Several transcription factors including Hand1/2, Tbx5, Osr1, FoxF1, Prrx1, Mesp1, and Etv2 are expressed in LPM territories and play overlapping roles in cell fate determination (Chal and Pourquié, 2017;Davidson and Zon, 2004; Takasato and Little, 2015), albeit not always with conserved function (Yabe et al., 2016). Anterior-to-posterior expression domains of select transcription factors including Tbx1/10 and Hand are conserved in lampreys and even in the basal cephalochordate amphioxus that lacks major LPM-derived organ systems (Onimaru et al., 2011). These observations raise the possibility of the existence of an ancient upstream program that delineates the prospective LPM domain.In zebrafish, the LPM emerges from the ventral half of the embryo and becomes readily detectable as a patchwork of bilateral gene expression domains at the end of gastrulation (Davidson and Zon, 2004). hand2 expression marks in the anterior LPM (ALPM) the heart field and pectoral fin precursors, and a lateral-most domain within the posterior LPM (PLPM) (Perens et al., 2016; Yelon et al., 2000), wh...
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