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

Abstract

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, 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 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), alpha‐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.

Thyroid hormone action during brain development: More questions than answers

“…In vitro experiments have revealed evidence for cell-autonomous action of thyroid hormone at least for Purkinje cells, granule cells and astrocytes (Trentin et al, 2001;Heuer and Mason, 2003). In addition, various growth factors important for cerebellar development such as the neurotrophins BDNF and NT3 (Alvarez-Dolado et al, 1994;Koibuchi et al, 1999), Igf1 (Elder et al, 2000), extracellular matrix proteins involved in axonal guidance such as laminin (Farwell and Dubord-Tomasetti, 1999), tenascin (Alvarez-Dolado et al, 1998) and reelin (Alvarez-Dolado et al, 1999), as well as cell adhesion molecules such as NCAM and L1 (Iglesias et al, 1996;Alvarez-Dolado et al, 2000) are produced in a first or even second order response to thyroid hormone A c c e p t e d M a n u s c r i p t 9 indicating a plethora of possibilities by which thyroid hormone directs neuronal differentiation. In addition, thyroid hormone cannot only act in a so-called "genomic" manner by regulating gene expression via nuclear thyroid hormone receptors but it can also exert very rapid effects by e.g.…”

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

“…These genes include the myelin genes in oligodendrocytes (Sutcliffe, 1988;Schoonover et al, 2004), glial fibrillary acidic protein and vimentin expression in astrocytes (Lima et al, 1998), extracellular matrix proteins and adhesion molecules involved in neuronal migration and differentiation and in axonal growth, guidance and fasciculation. These adhesion molecules include tenascin C, laminin, L1 and NCAM (Iglesias et al, 1996;Alvarez-Dolado et al, 1998;Farwell and Dubord-Tomasetti, 1999a;Farwell and DubordTomasetti, 1999b;Alvarez-Dolado et al, 2000). THs also control the expression of many proteins that have roles in terminal cell differentiation, including cell cycle regulators, cytoskeletal proteins, neurotrophins and neurotrophin receptors.…”

Functional Analysis of Basic Transcription Element Binding Protein by Gene Targeting Technology

“…However, relatively little is known about the functional role of T 3 in brain development because the information regarding the target genes is limited. Differential hybridization was performed to search for T 3 -regulated genes in vertebrates such as the frog and the rat (3,4,5,10,11,24,32,35), and the BTEB gene was identified as one of the most distinct T 3 -responsive genes in the Xenopus tadpole (3,4). The enhanced expression of the BTEB gene in response to T 3 has also been confirmed in the developing CNS of the rodent and was demonstrated to be a transcriptional event by a nuclear run-on assay (4).…”