TOPIC: Thyroid development
Title: Early developmental specification of the thyroid gland depends on han-expressing surrounding tissue and on FGF signals.
Authors: : Wendl T, Adzic D, Schoenebeck JJ, Scholpp S, Brand M, Yelon D, & Rohr KB.
Reference: Development 134: 2871-2879, 2007 (doi:10.1242/dev.02872)
In all vertebrates, the thyroid gland develops from the ventral floor of the anterior pharyngeal endoderm. Unravelling the molecular mechanisms of thyroid development is expected to help in understanding the mechanisms leading to thyroid dysgenesis, the major cause of congenital hypothyroidism. Development of the thyroid is comparable between fish and mammals on the molecular level. The thyroid-specific transcriptional programme, including the transcription factors Nkx2.1 (also known as Nk2.1a and Titf1a/TITF1), Pax8 and Hhex, is conserved with respect to expression patterns and function between zebrafish and mouse.
In this study, the authors used zebrafish as a model to investigate the initiation of thyroid development.
Material & Methods
Zebrafish harbouring mutations in the hands off ( han , hand2 ) and fgf8 genes were used to study the role of these genes in normal thyroid development.
Zebrafish han mutants displayed severely reduced or absent expression of thyroid-specific developmental genes ( titf1, pax8 ) concomitant with the complete loss of a functional gland. The han locus encodes the bHLH transcription factor Hand2 known to be expressed in cardiac mesoderm, the fin buds and the pharyngeal arches. The han s6 and han c99 alleles are null and hypomorphic alleles respectively, with han s6 displaying, accordingly, a stronger phenotype. In grafting experiments, the authors showed that han expression in the anterior plate mesoderm or cardiac mesoderm was crucial for thyroid specification. Thus, han gene was required in the tissue surrounding the thyroid for normal gland development. They further showed that FGF signalling was required for thyroid development in zebrafish, and that FGF-coated beads were able to restore thyroid development in han s6 mutants.
This study provides the first evidence towards understanding the role of surrounding tissue during thyroid specification.
Studies of transcription factors implicated in the regulation of thyroid-specific genes expressed in the adult gland have led to the identification of a limited number of genes involved in normal thyroid development: Nkx2.1 (also known as Nk2.1a and Titf1a/TITF1), Pax8, FoxE1 and Hhex. Despite the identification of mutations in rare cases with thyroid dysgenesis, the vast majority of thyroid developmental defects in human do not show mutations in these genes. In addition, thyroid dysgenesis does not lean itself to gene mapping by classical linkage studies, since most cases are sporadic. Indeed, the disease does not follow mendelian inheritance, nor does it obey to multigenic inheritance since monozygotic twins, as a rule, are discordant.
Confronted with these problems, groups aiming at understanding the mechanisms leading to thyroid dysgenesis are left with the reasonable option of studying the basic phenomena implicated in early thyroid specification and development. A logical approach has been to attempt identification of novel genes expressed more or less specifically in the thyroid bud. Whereas this endeavour is underway in several laboratories, the study by Wendl et al. demonstrates that genes expressed outside the thyroid anlage , within the surrounding mesenchyme, play an instructive role on the specification of the pharyngeal endoderm. By exploiting loss of function mutations together with grafting, fate mapping and experiments involving soaked beads and FGF signalling inhibitors, they demonstrate unequivocally that the transcription factor gene han , acting upstream of fgf8 , is required for induction of cell autonomous development thyroid genes like nxk2.1 . With the demonstration of the role of han expression in the anterior lateral plate mesoderm (aLPM), from which the heart later develops, the results of Wendl et al provide a convincing rationale for the close relation between cardiac and thyroid development, and also the observed association between cardiac and thyroid developmental defects.
As a final comment, it is worth noting that such kind of studies would be extremely difficult, if not impossible, to perform in the mouse. It advertises zebrafish as a fruitful model for exploration of genes/mechanisms involved in thyroid dysgenesi Summary and commentary prepared by Gilbert Vassart (related to Chapter 1 of TDM)