Zebrafish hhex, nk2.1a, and pax2.1 regulate thyroid growth and differentiation downstream of Nodal-dependent transcription factors

Abstract

During zebrafish development, the thyroid primordium initiates expression of molecular markers such as hhex and nk2.1a in the endoderm prior to pharynx formation. As expected for an endodermally derived organ, initiation of thyroid development depends on Nodal signalling. We find that it also depends on three downstream effectors of Nodal activity, casanova (cas), bonnie and clyde (bon), and faust (fau)/gata5. Despite their early Nodal-dependent expression in the endoderm, both hhex and nk2.1a are only required relatively late during thyroid development. In hhex and nk2.1a loss-of-function phenotypes, thyroid development is initiated and arrests only after the primordium has evaginated from the pharyngeal epithelium. Thus, like pax2.1, both hhex and nk2.1a have similarly late roles in differentiation or growth of thyroid follicular cells, and here, we show that all three genes act in parallel rather than in a single pathway. Our functional analysis suggests that these genes have similar roles as in mammalian thyroid development, albeit in a different temporal mode of organogenesis.

Developmental toxicity and alteration of gene expression in zebrafish embryos exposed to PFOS

“…hhex expression occurs up to 96 hpf and pax8 is expressed up to 7 days post-fertilization and is generally required for late differentiation of the follicular cells (Wendl et al, 2002). Overexpression of hhex results in an enlarged thyroid primordium, which suggests that hhex can promote growth of the thyroid primordium (Elsalini et al, 2003). In our study, PFOS treatment resulted in increased expression of hhex and pax8, which suggests that PFOS may induce thyroid gland development at early developmental stages in zebrafish.…”

“…For example, hhex and pax8 are required for the differentiation and formation of thyroid follicles and can be used as marker genes in the developing thyroid of zebrafish (Elsalini et al, 2003). pax8 is expressed in the developing thyroid of zebrafish throughout thyroid development, and double-in situ hybridization has shown that hhex and pax8 are expressed in thyroid precursor cells (Wendl et al, 2002).…”

Morphogenetics of early thyroid development

“…The data discussed earlier for Tbx1 mutant mice (Lania et al 2009) and similar findings in cyclops (a Nodal ligand), dHand, and fgf8 zebrafish mutants (Elsalini et al 2003, Wendl et al 2007 raise the possibility that the number of progenitors recruited to a thyroid fate may limit the final size of the thyroid gland by a similar mechanism. However, there are observations suggesting that embryonic thyroid growth not only depends on factors involved in preformation of the anlage in the endoderm but that later events in organogenesis also contribute.…”

Expression of sodium-iodide symporter mRNA in the thyroid gland of Xenopus laevis tadpoles: developmental expression, effects of antithyroidal compounds, and regulation by TSH

“…Three thyroid-specific transcription factors, Pax8, Nkx2$1, and FoxE1, have been shown to mediate the TSH/cAMP effects on gene transcription in mammalian thyroid follicular cells (Damante et al 2001), but very little is known about the role of thyroid-specific transcription factors in nonmammalian vertebrates (Wendl et al 2002, Elsalini et al 2003. Using the whole mount in situ hybridization, Nkx2$1 mRNA expression has been observed in the thyroid primordium of X. laevis embryos (Hollemann & Pieler 2000, Small et al 2000, but expression of Nkx2$1 mRNA in thyroid glands of metamorphosing tadpoles has not been resolved.…”