Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage.
Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4(-/-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A- and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important.
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrensk Academy at University of Gothenburg, Box 440, SE-40530 Göteborg, Sweden.
Louise
L
Andersson
Jessica
J
Westerlund
Shawn
S
Liang
Therese
T
Carlsson
Elena
E
Amendola
Henrik
H
Fagman
Mikael
M
Nilsson
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013961:Thyroid Gland / Q000033:anatomy & histology / Q000166:cytology* / Q000196:embryology*
C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D036122:Receptor, EphA4