The Tbx1 gene and the developing thyroid

Topic: New genes in the pathogenesis of thyroid disease

Title: The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning.

Authors: Fagman H, Liao J, Westerlund J, Andersson L, Morrow BE, & Nilsson M.

Reference: Human Molecular Genetics 16: 276-285, 2007



Thyroid dysgenesis is the major cause of congenital hypothyroidism in humans. The underlying molecular mechanism is unknown in most cases, but the frequent co-incidence of cardiac anomalies suggests that the thyroid morphogenetic process may depend on proper cardiovascular development. The T-box transcription factor Tbx1, which is the most probable gene for the 22q11 deletion syndrome (22q11DS/DiGeorge syndrome/velo-cardio-facial syndrome), has emerged as a central player in the coordinated formation of organs and tissues derived from the pharyngeal apparatus and the adjacent secondary heart field from which the cardiac outflow tract derives.


To determine that Tbx1 impacts greatly on the developing thyroid gland.


Observation of thyroid glands in utero from Tbx +/+ and Tbx -/- mice.


In late mutant embryos, the thyroid fails to form symmetric lobes but persists as a single mass of approximately one-fourth the normal size. The hypoplastic gland mostly attains a unilateral position resembling thyroid hemiagenesis. The data further suggest that failure of the thyroid primordium to reestablish contact with the aortic sac is a key abnormality preventing normal growth of the midline anlage along the third pharyngeal arch arteries. In normal development, this interaction may be facilitated by Tbx1-expressing mesenchyme filling the gap between the pharyngeal endoderm and the detached thyroid primordium.

The findings indicate that Tbx1 regulates intermediate steps of thyroid development by a non-cell-autonomous mechanism. Thyroid dysgenesis related to Tbx1 inactivation may explain an over-representation of hypothyroidism occurring in patients with the 22q11 deletion syndrome.


Congenital hypothyroidism (CH) is the most common endocrine disorder seen in children, with a prevalence of ~1/4000 live births. Subjects are usually identified at birth by neonatal screening programs, and early diagnosis & treatment prevent the neurological and somatic effects of neonatal hypothyroidism. There are two classes of CH, either with a goiter, or with dysgenesis ranging from agenesis to hemiagenesis and to ectopic location. Goitrous CH is usually due to a defect in the thyroglobulin gene, Na/I transporter, thyroperoxidase, thyroid oxidase 2, and Pendrin.

The molecular mechanisms of thyroid dysgenesis in humans are largely unknown. So far, genes encoding thyroid transcription factors that are required for normal thyroid development in mouse, i.e. Titf1/Nkx2.1 (also known as TTF-1) Foxe1 (also known as TTF-2) and Pax8, have been found to be mutated only in a small percentage of human cases. While some cases are likely to be polygenic, twin studies have suggested that epigenetic modifications, early mutations may be responsible. The association of other somatic abnormalities, specifically cardiac defects in some human subjects with thyroid dysgenesis, raises the possibility that certain genes responsible for organ pattering shared by different organs may be responsible. Such a gene might be -Sonic hedgehog- (Shh) which regulates mouse thyroid lobulation. The thyroid phenotype of -Shh- homozygous mutants resembles the hemiagenesis reported to occur in ~2/1000 newborns. Although -Shh- deficiency in humans is very rare, disruptions of common signalling pathways may lead to incomplete thyroid development. Tbx1 is a gene that is downstream of the Shh action. Bilateral growth of the midline thyroid buds at E11.5-12.5, constituting the start of the lobulation process, occurs along the course of the third pharyngeal arch arteries that will later form the segments of the carotid vessels which hug, bilaterally the thyroid lobes in adulthood. The protein encoded by Tbx1 is a transcription factor that plays a central role in pharyngeal arch development. Tbx1-/- mice have significant cardiac outflow tract malformations similar to those found in the 22q11 deletion syndrome.

The authors beautifully demonstrated that in the Tbx1-/- mice the thyroid does not establish proper contact with the aortic sac and subsequently the bilobation fails, resulting in a severely hypoplastic gland. Although most cases of thyroid agenesis or hemiagenesis are sporadic, there are several families reported with such anomalies. Neither the majority of sporadic or familial forms have a known molecular basis. This research raises the possibility of Tbx1 -/- as a candidate gene for thyroid agenesis.

( Summary and commentary prepared by Roy Weiss )

Present summary & commentary are related to Chapters N- 1 & 15 of the TDM

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