THYROID HORMONE-DEPENDENT TRANSCRIPTIONAL REPRESSION OF NEURAL CELL-ADHESION MOLECULE DURING BRAIN MATURATION

Thyroid hormone (T3) is a main regulator of brain development acting a s 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 bra in which are under the transcriptional control of T3, Six of them, inc luding the neural cell adhesion molecule NCAM, alpha-tubulin and four other unidentified sequences (RBA3, RBA4, RBB3 and RBB5) were found to be upregulated in the hypothyroid brain, whereas another (RBE7) was d ownregulated. Binding sites for the T3 receptor (T3R/c-erbA) were iden tified in the isolated clones by gel-shift and footprinting assays, Si tes in the NCAM (in an intron), alpha-tubulin (in an exon) and RBA4 cl ones mediated transcriptional regulation by T3 when inserted upstream of a reporter construct, However, no effect of the NCAM clone was foun d when located downstream of another reporter gene, Northern blotting and in situ hybridization studies showed a higher expression of NCAM i n the brain of postnatal hypothyroid rats, Since NCAM is an important morphoregulatory molecule, abnormal NCAM expression is likely to contr ibute to the alterations present in the brain of thyroid-deficient hum ans and experimental animals.