Morphogenesis of the thyroid gland

Abstract

Congenital hypothyroidism is mainly due to structural defects of the thyroid gland, collectively known as thyroid dysgenesis. The two most prevalent forms of this condition are abnormal localization of differentiated thyroid tissue (thyroid ectopia) and total absence of the gland (athyreosis). The clinical picture of thyroid dysgenesis suggests that impaired specification, proliferation and survival of thyroid precursor cells and loss of concerted movement of these cells in a distinct spatiotemporal pattern are major causes of malformation. In normal development the thyroid primordium is first distinguished as a thickening of the anterior foregut endoderm at the base of the prospective tongue. Subsequently, this group of progenitors detaches from the endoderm, moves caudally and ultimately differentiates into hormone-producing units, the thyroid follicles, at a distant location from the site of specification. In higher vertebrates later stages of thyroid morphogenesis are characterized by shape remodelling into a bilobed organ and the integration of a second type of progenitors derived from the caudal-most pharyngeal pouches that will differentiate into C-cells. The present knowledge of thyroid developmental dynamics has emerged from embryonic studies mainly in chicken, mouse and more recently also in zebrafish. This review will highlight the key morphogenetic steps of thyroid organogenesis and pinpoint which crucial regulatory mechanisms are yet to be uncovered. Considering the coincidence of thyroid dysgenesis and congenital heart malformations the possible interactions between thyroid and cardiovascular development will also be discussed.

Development of the thyroid gland

“…Studies in mice indicate that Foxe1 promotes the migration of thyroid precursor cells (De Felice et al, 1998;Parlato et al, 2004). However, the mechanism by which this occurs in vivo is unknown; migration of the bud still occurs, albeit incompletely, in Pax8 −/− embryos in which Foxe1 expression is undetectable, so it is likely that other, presumably non-cell-autonomous, factors contribute to migration (for a more detailed discussion of this, see Fagman and Nilsson, 2010). The expression profile of Foxe1-regulated genes has been studied in a rat thyroid cell line (Fernandez et al, 2013).…”

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

“…The PAX8 gene at 2q12-q14 is among the genes involved in thyroid gland development and, more specifically, in the proliferation and differentiation of thyroxine (T 4 )-producing follicular cells (4,5). PAX8 protein expression starts at the third gestational week in the human embryo and continues until adulthood (6,7,8,9,10). In thyrocytes, PAX8 contributes to proper timing of the switch from progenitor cell proliferation to the initiation of terminal differentiation programs marked by the expression of genes such as those encoding thyroglobulin, thyroperoxidase (TPO), and sodium/iodide symporter (8,11).…”

Morphogenetics of early thyroid development

“…1) in which progenitor cells expressing four critical transcription factors, NKX2-1, PAX8 (or Pax2.1a in zebrafish), FOXE1, and HHEX, assemble to form the thyroid bud (Fagman & Nilsson 2010). The growing bud subsequently delaminates from the pharyngeal endoderm and moves downward to the final anatomical position of the thyroid, a process that also involves incorporation of the ultimobranchial bodies whereby C-cell precursors are brought to the thyroid.…”

“…Finally, current views on the causes of TD in human patients and some aspects of embryonic stem (ES) cells will be briefly considered. For recent comprehensive reviews on thyroid morphogenesis in the most important animal models (mice, chicken, and zebrafish), see Porazzi et al (2009) andNilsson (2010).…”

“…Early thyroid development in mice depends on the conjoined activity of NKX2-1, PAX8, FOXE1, and HHEX to proceed normally (De Felice & Di Lauro 2007, Fagman & Nilsson 2010. However, neither of these Gut tube Figure 1 Organ bud outgrows along the anterior-posterior axis of the embryonic gut tube.…”