Endocrine Abstracts

Congenital hypothyroidism (CH) is one of the most frequent congenital diseases. In 85% of cases, this condition is due to thyroid dysgenesis (TD) whose phenotype - thyroid absent or ectopically located and/or severely reduced in size - clearly represent disturbances during gland organogenesis. Some years ago we discovered that three transcription factors, TTF-1, TTF-2 and Pax-8, are expressed not only in mature thyroid cells but also in their precursors. Work in animal models and in patients with TD has demonstrated that mutations in these genes result in TD. However, only a very small proportion of TD patients carries mutation in either of these three genes. We are now searching for additional candidate genes that could be involved in this disease.

We generated TTF-2-/- mice and found that in embryos homozygous for the null allele the thyroid bud forms but it does not migrate from the floor of the pharynx. To elucidate the molecular mechanisms underlying this phenomenon, we have decided to identify the target genes of TTF-2. We are using a strategy based on Laser Capture Microdissection to isolate thyroid precursor cells from tissue sections of wild type and TTF-2 null mice. mRNAs differently expressed in wild type and mutated embryos will provide us with a tool to identify specific genes regulated by TTF-2 and potential candidate in thyroid development defects.

The apparent sporadic appearance of congenital hypothyroidism could suggest that, at least in some cases, this disease could be caused by polygenic defects.

We have generated mice double heterozygous titf1+/- pax8+/-. In these animals thyroid function is impaired. This reveals, for the first time, that CH can be a multifactorial disease.