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Revising the embryonic origin of thyroid C cells in mice and humans

Journal article
Authors Ellen Johansson
Louise Andersson
Jessica Örnros
Therese Carlsson
Camilla Ingeson-Carlsson
Shawn Liang
Jakob Dahlberg
Svante Jansson
Luca Parrillo
Pietro Zoppoli
Guillermo O Barila
Daniel L Altschuler
Daniela Padula
Heiko Lickert
Henrik Fagman
Mikael Nilsson
Published in Development (Cambridge, England)
Volume 142
Issue 20
Pages 3519-3528
ISSN 1477-9129
Publication year 2015
Published at Institute of Biomedicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 3519-3528
Language en
Links dx.doi.org/10.1242/dev.126581
Subject categories Surgery

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 implicates 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. In similarity with many gut endoderm derivatives embryonic C cells were found to co-express 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. Contrasting embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment down-regulated Foxa2 foregoing epithelial-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.

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