Volume 21, Issue 2, June 2005

Table of Contents 21-2

Developmental Expression Patterns of Human Thyroid Transcriptional Regulators

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To further the understanding of thyroid dysgenesis, the most common cause of congenital hypothyroidism, Trueba and colleagues examined the developmental expression patterns of human thyroid transcriptional regulators by in situ hybridization and immunohistochemistry in tissues obtained from legally terminated pregnancies. They focused on 3 factors: PAX8, TITF1 (also known as Nkx2a, Ttf-1 or T/ebp) and FOXE1 (Ttf-2 or Titf-2). These 3 factors lead to thyroid dysgenesis in knock-out mouse models and have been found to cause congenital hypothyroidism when mutated in humans. The PAX8 gene was strongly expressed in median thyroid anlagen (from pharyngeal primordium) and laterally ectodermic region of the fourth pharyngeal arch, thyroglossal duct cells, ultimobranchial body and in later fetal follicular cells. It maintained follicular cell phenotype by activating thyroperoxidase, sodium/iodide symporter and thyroglobulin genes. The expression in thyroglossal duct cells suggested that the track was created by the migrating thyroid anlagen (rather than a pre-established pathway through which the thyroid migrated). This may explain why cells of thyroglossal duct remnants can differentiate into follicular cells to create follicle- and colloid-containing cysts. Additionally, PAX8 gene had an extra-thyroid expression on the otic vesicle, central nervous system (midbrain-hindbrain boundary, spinal cord) and the developing kidney (metanephric blastema, ureteric bud and their derivatives). The clinical correlates of the PAX8 gene have been found in congenital hypothyroid patients who also presented either unilateral renal agenesis or left-sided ureteropelvic obstruction. No PAX8^-/- humans have been reported with bilateral renal agenesis (? lethal phenotype form). However, no CNS defects were seen in knock-out mice and heterozygote PAX8 ^+/- humans have been detected.

The TITF1 gene was weakly expressed in the median thyroid primordium and later fetal thyroid. The extra-thyroid expression was limited to the forebrain (hypothalamic floor and infundibulum, developing basal ganglia territory) and lung epithelial cells which became progressively restricted to distal branches, reducing surfactant production. The clinical correlates of the TITF1 mutations were hypotonia and dyskinesia, changes in basal ganglia and pituitary gland and postnatal respiratory distress syndrome.

The FOXE1 gene had a weak expression in thyroid primordium and gland throughout development and the extra-thyroid expression was seen in the thymus and in the oropharyngeal, tracheal and esophageal epithelium. The clinical correlates were seen in patients with thyroid dysgenesis and cleft palate as well as knock-out mice. There were no thymic or immunologic abnormalities yet reported.The thyroglobulin protein promoter contained binding sites for PAX8, TITF1 and FOXE1, but thyroglobulin was not produced until the thyroid gland reached its final position.

Trueba SS, Auge J, Mattei G, et al. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. J Clin Endocrinol Metab. 2005;90:455-462

Editor’s Comment: This paper is an excellent example of bench-to-bedside applications. It also points out that, despite the power of knock-out mouse models for explaining physiology, caution should be taken in extrapolating to humans as species differences occur. For a recent review of congenital hypothyroidism and its etiologies, see reference 1.Another genetic cause of congenital hypothyroidism, not listed in this paper or the review, is inactivating mutation of the gene encoding the TSH receptor; 2 siblings with compound heterozygosis had severe congenital hypothyroidism with apparent athyreosis, while their non-consanguineous, hemizygous parents had either normal thyroid function or compensated hypothyroidism with mild thyroid hypoplasia.

Adda Grimberg, MD

Reference - (linked to )

1. Gruters A, Krude H, Biebermann H. Eur J Endocrinol 2004;151 Suppl 3:U39-44.
2. Park SM, Clifton-Bligh RJ, Betts P, Chatterjee VK. Clin Endocrinol 2004;60:220-227.

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