RT Journal Article
SR Electronic
T1 Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.11.355693
DO 10.1101/2020.11.11.355693
A1 Karin D. Prummel
A1 Helena L. Crowell
A1 Susan Nieuwenhuize
A1 Eline C. Brombacher
A1 Stephan Daetwyler
A1 Charlotte Soneson
A1 Jelena Kresoja-Rakic
A1 Manuel Ronner
A1 Agnese Kocere
A1 Alexander Ernst
A1 Zahra Labbaf
A1 David E. Clouthier
A1 Anthony B. Firulli
A1 Héctor Sánchez-Iranzo
A1 Rebecca O’Rourke
A1 Erez Raz
A1 Nadia Mercader
A1 Alexa Burger
A1 Emanuela Felley-Bosco
A1 Jan Huisken
A1 Mark D. Robinson
A1 Christian Mosimann
YR 2020
UL http://biorxiv.org/content/early/2020/11/11/2020.11.11.355693.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.