Firulli, A. B. | Search bioRxiv

bioRxiv2021

GATA3 is essential for separating patterning domains during facial morphogenesis

Neural crest cells (NCCs) within the mandibular and maxillary portions of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the Hinge and Caps model of facial development, signals from both ventral prominences, referred to as the caps, pattern the adjacent tissues while the intervening region, known as the hinge, maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here we show that disruption of Gata3 in mouse embryos leads to hemifacial microsomia, facial bone hypoplasia and syngnathia (bony fusion of the upper and lower jaws). These changes are preceded by gene expression changes in post-migratory NCCs around the maxillomandibular junction (the hinge). GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development. Summary StatementLoss of Gata3 leads to BMP-mediated disruption of Fgf8 expression at the maxillomandibular junction during development, resulting in later fusion of the upper and lower jaws.

developmental biology↗

bioRxiv2020

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

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.

developmental biology↗