Thyroid hormone-dependent transcriptional repression of neural cell adhesion molecule during brain maturation

Thyroid hormone (T3) is a main regulator of brain development acting as a transcriptional modulator. However, only a few T3-regulated brain genes are known. Using an improved whole genome PCR approach, we have isolated seven clones encoding sequences expressed in neonatal rat brain which are under the transcriptional control of T3. Six of them, including the neural cell adhesion molecule NCAM, α-tubulin and four other unidentified sequences (RBA3, RBA4, RBB3 and RBB5) were found to be upregulated in the hypothyroid brain, whereas another (RBE7) was downregulated. Binding sites for the T3 receptor (T3R/c-erbA) were identified in the isolated clones by gel-shift and footprinting assays. Sites in the NCAM (in an intron), α-tubulin (in an exon) and RBA4 clones mediated transcriptional regulation by T3 when inserted upstream of a reporter construct. However, no effect of the NCAM clone was found when located downstream of another reporter gene. Northern blotting and in situ hybridization studies showed a higher expression of NCAM in the brain of postnatal hypothyroid rats. Since NCAM is an important morphoregulatory molecule, abnormal NCAM expression is likely to contribute to the alterations present in the brain of thyroid-deficient humans and experimental animals.