Early thyroid development requires a Tbx1–Fgf8 pathway

Abstract

The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. The many derivatives of the pharyngeal apparatus develop at similar times and sometimes from common cell types, explaining why many syndromic disorders express multiple birth defects affecting different structures that share a common pharyngeal origin. Thus, different derivatives may share common genetic networks during their development. Tbx1, the major gene associated with DiGeorge syndrome, is a key player in the global development of the pharyngeal apparatus, being required for virtually all its derivatives, including the thyroid. Here we show that Tbx1 regulates the size of the early thyroid primordium through its expression in the adjacent mesoderm. Because Tbx1 regulates the expression of Fgf8 in the mesoderm, we postulated that Fgf8 mediates critical Tbx1-dependent interactions between mesodermal cells and endodermal thyrocyte progenitors. Indeed, conditional ablation of Fgf8 in Tbx1-expressing cells caused an early thyroid phenotype similar to that of Tbx1 mutant mice. In addition, expression of an Fgf8 cDNA in the Tbx1 domain rescued the early size defect of the thyroid primordium in Tbx1 mutants. Thus, we have established that a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid.

Morphogenesis of the thyroid gland

“…This suggests that the final thyroid size is constrained by the number of cells initially recruited to a thyroid fate. Other examples of development of thyroid hypoplasia associated with a reduced size of the early primordium are the hand2 hypomorphic allele (han c99 ) and fgf8 mutant (ace) in zebrafish (Wendl et al, 2007) and the Tbx1 null mouse embryo (Lania et al, 2009), the effects of which will be discussed in further detail below. Direct evidence for this novel concept of developmental regulation comes from a recent study demonstrating that the number of progenitor cells in the pancreatic bud is limiting final organ size (Stanger et al, 2007).…”

“…Disruption of the Shp2-binding sites of the FGF receptor (FGFR) docking protein FRS2 causes thyroid hypoplasia (Kameda et al, 2009), indicating that embryonic thyroid growth is influenced by FGFR signaling. In view of the significant impact genetic deletion of Tbx1, a transcriptional regulator of FGFs (Vitelli et al, 2002), has on thyroid size in late morphogenesis (Fagman et al, 2007), early thyroid development was investigated in embryos where Tbx1 was either generally deleted or specifically targeted in the mesoderm (Mesp1 Cre/+ ;Tbx1 fl/-) (Lania et al, 2009). This showed that proliferation in the E8.5 foregut endoderm and the number of cells in the thyroid placode is reduced by mesodermal ablation of Tbx1 suggesting a diminished thyroid precursor cell pool size.…”

“…However, it is not yet clear if endodermal cells are the direct targets of this Fgf8 signal as deletion of FGFR1 and FGFR2 in the endoderm does not produce a thyroid defect (Lania et al, 2009). M a n u s c r i p t…”

“…As the thyroid placode in this situation was found not to be enlarged, this suggests that hhex regulates cell proliferation after the pool of endoderm progenitors destined to a thyroid fate has been specified. This is of fundamental interest taking into account the recent findings in mouse that the number of progenitors that populates the placode determines the embryonic thyroid size and is controlled by Tbx1 expressed in the mesoderm (Lania et al, 2009).…”

“…Taken together, studies in zebrafish and mice firmly establish that FGF signaling is crucial to early thyroid development and that the cardiac mesoderm is a probable source of inductive and permissive signals (Wendl et al, 2007;Lania et al, 2009). However, the exact role of FGF in early stages of thyroid development needs to be further clarified.…”