An integrated regulatory network controlling survival and migration in thyroid organogenesis

Abstract

The thyroid gland originates from the ventral floor of the foregut as a thickening of the endodermal cell layer. The molecular mechanisms underlying the early steps of thyroid morphogenesis are not known. Gene targeting experiments have contributed to the identification of several transcription factors, in general playing a role in the proliferation, survival, and migration of the thyroid cell precursors. The experiments reported here analyze the expression of the transcription factors Titf1, Hhex, Pax8, and Foxe1 in the thyroid primordium of null mutants of each of them. We found that most of these transcription factors are linked in an integrated regulatory network, each of them controlling the presence of other members of the network. The expression of Foxe1 is regulated in an intriguing fashion as it is strongly dependent on the presence of Pax8 in thyroid precursor cells, while the expression of the same gene in the pharyngeal endoderm surrounding the primordium is dependent on Sonic hedgehog (Shh)-derived signaling. Moreover, by the generation of mouse mutants expressing Foxe1 exclusively in the thyroid primordium, we provide a better understanding of the role of Foxe1 in these cells in order to acquire the competence to migrate into the underlying mesenchyme. In conclusion, we provide the first evidence of gene expression programs, controlled by a hierarchy of transcription factors expressed in the thyroid presumptive gut domain and directing the progression of thyroid morphogenesis.

Morphogenesis of the thyroid gland

“…However, the size of the early thyroid bud in Shh deficient mice is comparable to that of the wildtype anlage (Fagman et al, 2004;Parlato et al, 2004). Instead Shh may prevent ectopic differentiation of thyroid cells in more distant parts of the foregut and its derivatives as the prospective trachea (Fagman et al, 2004).…”

“…The significance is illustrated by the fact that more widespread Shh repression leads to ectopic pancreatic differentiation and that targeted over-expression of Shh in the prospective pancreas primordium partly diverts the lineage program of progenitors towards an intestinal fate (Apelqvist et al, 1997). That Shh might play a similar role in thyroid development by restricting the endoderm adopting a thyroid fate is suggested by the finding that Shh is strongly expressed in the adjacent foregut epithelium but not at all in the Nkx2-1-expressing progenitor cells forming the thyroid placode (Fagman et al, 2004;Parlato et al, 2004;Moore-Scott and Manley, 2005).…”

“…The defect is related to the fact that Nkx2-1, as in the thyroid, is expressed in progenitor cells from the time of bud formation and onwards throughout lung development, regulating sequentially branching morphogenesis (Minoo et al, 1995) and alveolar maturation (Bohinski et al, 1994). The thyroid defect is also severe, as the thyroid bud is hypoplastic and regresses completely by E12-E13 (Kimura et al, 1999;Parlato et al, 2004). However, formation of the thyroid placode and subsequent pseudostratification of the early bud take place seemingly normally (Parlato et al, 2004), indicating that Nkx2-1 is required to complete budding.…”

“…The thyroid defect is also severe, as the thyroid bud is hypoplastic and regresses completely by E12-E13 (Kimura et al, 1999;Parlato et al, 2004). However, formation of the thyroid placode and subsequent pseudostratification of the early bud take place seemingly normally (Parlato et al, 2004), indicating that Nkx2-1 is required to complete budding. In zebrafish embryos loss of the Nkx2-1 ortholog nk2.1a leads to disturbed thyroid development in a fashion similar to that demonstrated in the mouse mutant .…”

“…In mutants the hepatic endoderm remains as a columnar, simple epithelium indicating that Hhex is required for interkinetic nuclear migration and liver bud formation (Bort et al, 2006). In contrast, although thyroid bud outgrowth fails the thyroid placode is readily pseudostratified in the absence of Hhex (Parlato et al, 2004).…”