Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse.
Thyroid dysgenesis encountered in 85% of patients with congenital hypothyroidism is a morphologically heterogeneous condition with primarily unknown pathogenesis. Here we identify sonic hedgehog (Shh) as a novel regulator of thyroid development. In Shh knockout mice the thyroid primordium is correctly specified in the pharyngeal endoderm, but budding and dislocation are slightly delayed. In late development the thyroid fails to form a bilobed gland. Instead a single thyroid mass is found unilaterally and mostly to the left of the midline. Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation. Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-/- embryos. The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin. Shh mRNA is not expressed in the thyroid precursor cells at any developmental stage. The results indicate that Shh signaling indirectly governs the symmetric bilobation of the thyroid during late organogenesis. Shh also seems to repress inappropriate thyroid differentiation in nonthyroid embryonic tissues. This study provides clues to the molecular mechanisms that might be dysregulated in thyroid hemiagenesis and development of ectopic thyroid tissue outside the thyroglossal duct.
Fagman
Henrik
H
Institute of Anatomy and Cell Biology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. henrik.fagman@anatcell.gu.se
Grände
Mats
M
Gritli-Linde
Amel
A
Nilsson
Mikael
M
D000818:Animals; D002454:Cell Differentiation; D004848:Epithelium / Q000473:pathology; D017353:Gene Deletion; D053823:Hedgehog Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013954:Thyroglobulin / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014132:Trachea / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*
D053823:Hedgehog Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D013954:Thyroglobulin