Crucial role for type II iodothyronine deiodinase in the metabolic coupling between glial cells and neurons during brain development.

Mammalian brain maturation and function are under the control of thyroid hormones which regulate and synchronize several developmental processes in the central nervous system (CNS), such as cell migration, neuronal differentiation, outgrowth of neuronal processes, acquisition of neuronal polarity, synaptogenesis and myelin formation. Moreover, thyroid hormones seem to be crucial for the cytoarchitecture of the neocortex and the cerebellum. In recent years it has been demonstrated that both the neurons and the oligodendrocytes are direct cellular targets of thyroid hormones during brain development. These cell types express thyroid hormone receptors which bind the active hormone 3,5,3 0 -tri-iodothyronine (T3), leading to the expression of specific neuronal genes. Therefore, T3 exerts an important role in the control of the timed coordination of different developmental events in the central nervous system, in large part by regulating gene expression and cell differentiation. As a consequence, it is not surprising that tightly controlled amounts of T3 are required during the critical period of construction of the neuronal network. In effect, thyroid hormone deficiency during this period leads to severe alterations in the anatomy and function of the brain (cretinism) if replacement therapy is not performed soon after birth. Although thyroxine (T4) is about 8- to 10-fold more abundant than T3 in the thyroidal secretion, the latter is the active hormone accounting for most of the biological potency of the secretion. T3 present in the brain is essentially produced by partial deiodination of T4. This reaction is catalyzed by the type II iodothyronine 5 0 -deiodinase (5 0 D-II). This enzyme belongs to a new family of eukariotic selenoproteins recently identified and cloned (1‐3). 5 0 D-II is able to catalyze deiodination of T4 exclusively on the phenolic ring to yield T3 and is highly expressed in rat brain, anterior pituitary, brown adipose tissue and in placenta. Croteau and coworkers have also demonstrated similar results in human tissues (2). Northern blot analysis revealed the presence of 5 0 D-II transcripts in fetal and adult brain, in heart, in skeletal muscles and in placenta. The finding of elevated 5 0 D-II activity in the rat and human CNS provides evidence of the essential role of this enzyme in the brain in supplying adequate amounts