title: The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities.
abstract: The fate of pluripotent cells in early mouse embryos is controlled by graded Nodal signals that are activated by the endoproteases Furin and Pace4. Soluble forms of Furin and Pace4 cleave proNodal in vitro and after secretion in transfected cells, but direct evidence for paracrine activity in vivo is elusive. Here, we show that Furin and Pace4 are released by the extraembryonic microenvironment, and that they cleave a membrane-bound reporter substrate in adjacent epiblast cells and activate Nodal to maintain pluripotency. Secreted Pace4 and Furin also stimulated mesoderm formation, whereas endoderm was only induced by Pace4, correlating with a difference in the spatiotemporal distribution of these proteolytic activities. Our analysis of paracrine Furin and Pace4 activities and their in vivo functions significantly advances our understanding of how the epiblast is patterned by its microenvironment. Adding cell-cell communication to the pleiotropic portfolio of these proteases provides a new framework to study proprotein processing also in other relevant contexts.
authors: Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, CH-1015 Lausanne, Switzerland.
authors: Daniel
authors: D
authors: Mesnard
authors: Martyn
authors: M
authors: Donnison
authors: Christophe
authors: C
authors: Fuerer
authors: Peter L
authors: PL
authors: Pfeffer
authors: Daniel B
authors: DB
authors: Constam
mesh_terms: D000818:Animals; D004475:Ectoderm / Q000196:embryology; D004707:Endoderm / Q000187:drug effects / Q000196:embryology; D005321:Extraembryonic Membranes / Q000201:enzymology; D045683:Furin / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005855:Germ Layers / Q000201:enzymology*; D008648:Mesoderm / Q000187:drug effects / Q000196:embryology; D051379:Mice; D055457:Nodal Protein / Q000378:metabolism; D019899:Paracrine Communication; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D055457:Nodal Protein; C526008:Nodal protein, mouse; C513086:Pcsk6 protein, mouse; D043484:Proprotein Convertases; D045683:Furin