Postotic and preotic cranial neural crest cells differently contribute to thyroid development

Abstract

Thyroid development and formation vary among species, but in most species the thyroid morphogenesis consists of five stages: specification, budding, descent, bilobation and folliculogenesis. The detailed mechanisms of these stages have not been fully clarified. During early development, the cranial neural crest (CNC) contributes to the thyroid gland. The removal of the postotic CNC (corresponding to rhombomeres 6, 7 and 8, also known as the cardiac neural crest) results in abnormalities of the cardiovascular system, thymus, parathyroid glands, and thyroid gland. To investigate the influence of the CNC on thyroid bilobation process, we divided the CNC into two regions, the postotic CNC and the preotic CNC (from the mesencephalon to rhombomere 5) regions and examined. We found that preotic CNC-ablated embryos had a unilateral thyroid lobe, and confirmed the presence of a single lobe or the absence of lobes in postotic CNC-ablated chick embryos. The thyroid anlage in each region-ablated embryos was of a normal size at the descent stage, but at a later stage, the thyroid in preotic CNC-ablated embryos was of a normal size, conflicting with a previous report in which the thyroid was reduced in size in the postotic CNC-ablated embryos. The postotic CNC cells differentiated into connective tissues of the thyroid in quail-to-chick chimeras. In contrast, the preotic CNC cells did not differentiate into connective tissues of the thyroid. We found that preotic CNC cells encompassed the thyroid anlage from the specification stage to the descent stage. Finally, we found that endothelin-1 and endothelin type A receptor-knockout mice and bosentan (endothelin receptor antagonist)-treated chick embryos showed bilobation anomalies that included single-lobe formation. Therefore, not only the postotic CNC, but also the preotic CNC plays an important role in thyroid morphogenesis.

A branching morphogenesis program governs embryonic growth of the thyroid gland

“… Teshima et al (2016) also found that conditional inactivation of Fgf10 in neural crest ( Wnt1Cre;Fgf10 fl/fl mutants) reduced thyroid size although to a lesser degree than after global inactivation, suggesting that mesodermal Fgf10 also likely contributes to thyroid development. Nonetheless, this study and ours localized Fgf10 to crest-derived mesenchyme that invests the thyroid primordium, which provides mechanistic insight to thyroid developmental defects reported to occur after neural crest ablation ( Bockman and Kirby, 1984 ; Kameda et al, 2013 ; Maeda et al, 2016 ). It is important to note that the phenotype of Fgf10 null mutant mice does not comprise thyroid agenesis, which was originally reported ( Ohuchi et al, 2000 ) and thus erroneously stated in a recent review paper on the multifunctional role of Fgf10 in development ( Itoh, 2016 ).…”

Development of the thyroid gland

“…It should be noted that, although important for morphogenesis, embryonic vessels do not have an inductive role for the thyroid, as shown in the zebrafish cloche mutant which is devoid of any vascularization . Classical ablation studies in chick embryos have also revealed a role for cranial neural crest in thyroid development (Bockman and Kirby, 1984), and more recent findings indicate that subpopulations of neural crest cells differentially influence the distinct stages of chick thyroid morphogenesis (Maeda et al, 2016). This again highlights that the embryonic thyroid shifts microenvironments more than once before reaching its final position in the neck, and thus is likely -as we indeed highlight below and as summarized in Fig.…”

“…Finally, it should be noted that ablation studies in chick embryos have shown that neural crest-derived mesenchyme regulates thyroid lobe formation independently of embryonic vessels (Maeda et al, 2016). A thyroid lobe defect may thus appear even though the pharyngeal arch arteries seemingly develop normally.…”

The role of teratogens in neural crest development

“…Disruption of this signaling results in abnormally small mandibular and hyoid arches, absence of the NC‐derived Meckel's cartilage, small tongue, and malformed or missing middle ear elements (Clouthier et al, ; Pla & Larue, ; Yanagisawa et al, ). It was also found that Edn1/EdnrA ‐knockout mouse and bosentan‐treated chick embryos showed an alteration in the bilobation process during thyroid development, with some embryos displaying only single‐lobe formation (Kempf et al, ; Maeda et al, ). Additionally, defects in NC migration to pharyngeal arches 3, 4 and 6 caused by Edn1/Ednra inhibitors give rise to cardiac outflow tract malformations (Kurihara et al, ; Pla & Larue, ).…”