title: Revising the embryonic origin of thyroid C cells in mice and humans.
abstract: Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail-chick chimeras involving fate mapping of neural crest cells to the ultimobranchial glands that regulate Ca(2+) homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development involves a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing, we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. Like many gut endoderm derivatives, embryonic C cells were found to coexpress pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis, differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo, consistent with a growth-promoting role of Foxa1. In contrast to embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment downregulated Foxa2, foregoing epithelial-to-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development.
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Ellen
authors.initials: E
authors.lastname: Johansson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Örnros
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Carlsson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Ingeson-Carlsson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden.
authors.forename: Shawn
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Dahlberg
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Jansson
authors.affiliation: IRGS, Biogem, Ariano Irpino (AV), 83031, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Parrillo
authors.affiliation: Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Avenue, New York, NY 10031, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Guillermo O
authors.initials: GO
authors.lastname: Barila
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Altschuler
authors.affiliation: Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, German Research Center for Environmental Health GmgH, Ingolstaedter Landstraße 1, Munich 85764, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Padula
authors.affiliation: Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, German Research Center for Environmental Health GmgH, Ingolstaedter Landstraße 1, Munich 85764, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
authors.affiliation: Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Fagman
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden mikael.nilsson@gu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D004707:Endoderm / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009432:Neural Crest / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology; D013961:Thyroid Gland / Q000166:cytology* / Q000196:embryology*; D013964:Thyroid Neoplasms / Q000378:metabolism
chemical_list: C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D002116:Calcitonin; D002118:Calcium
keywords: Endoderm; Foxa1; Foxa2; Medullary thyroid cancer; Neural crest; Neuroendocrine