Human Molecular Genetics Advance Access originally published online on December 12, 2006
Human Molecular Genetics 2007 16(3):276-285; doi:10.1093/hmg/ddl455
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The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning
1 Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy at Göteborg University, SE-40530, Göteborg, Sweden and 2 Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
* To whom correspondence should be addressed at: Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy at Göteborg University, Box 420, SE-40530 Göteborg, Sweden. Tel: +46 317863321; Fax: +46 317863322; Email: henrik.fagman{at}anatcell.gu.se
Received August 15, 2006; Revised October 27, 2006; Accepted December 1, 2006
Thyroid dysgenesis is the major cause of congenital hypothyroidism in humans. The underlying molecular mechanism is in most cases unknown, 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. Here, we show that Tbx1 impacts greatly on the developing thyroid gland, although it cannot be detected in the thyroid primordium at any embryonic stage. Specifically, in Tbx1–/– mice, the downward translocation of Titf1/Nkx2.1-expressing thyroid progenitor cells is much delayed. In late mutant embryos, the thyroid fails to form symmetric lobes but persists as a single mass approximately one-fourth of 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 re-establish 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 overrepresentation of hypothyroidism occurring in patients with the 22q11DS.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.