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Institut National de la Santé et de la Recherche Médicale 75654 Paris Cedex 13, France
Address all correspondence and requests for reprints to: Bertrand Saunier, Molecular Structure Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, the National Institutes of Health, 4 Center Drive, Room 237, Bethesda, Maryland 20892-0445. E-mail: bsaunier{at}niaid.nih.gov.
Although normal brain development is strongly determined by genetic factors, seemingly minor environmental or congenital factors can interfere with its process and alter its conclusion. In this issue of Endocrinology, Goodman and Gilbert (1) report that a neuronal ectopia had developed in the brain of young rats upon induction of a mild hypothyroidism starting the first week of gestation. It has long been recognized in humans that, if not corrected by appropriate hormonal replacement, congenital hypothyroidism resulted in cretinism. Since then, studies have shown that maternal hypothyroidism or deficit in iodine was, in fact, greatly involved in neurodevelopmental disorders for her offspring (2, 3). There is now evidence for fetal brain developmental abnormalities resulting from both early and late maternal hormonal deficits (4, 5). Discordant hypotheses have been proposed regarding the stage of development at which a thyroid hormone deficit had the greatest impact. Neuronal migration is impaired by a lack of thyroid hormones, the consequences of which greatly depend on developmental stages and regions of the fetal brain (6, 7). By delaying the proliferation of various neural subpopulations and disorganizing neuronal networks before delivery, even if properly treated after birth, congenital hypothyroidism will still result in impaired cognitive functions (8).
In rats, delivery normally occurs after 21 d of gestation, at a stage of neural development that, in humans, would roughly correspond to mid-pregnancy. We have, therefore, to keep in mind that the consequences of congenital hypothyroidism cannot exactly be the same in both species (4). Nevertheless, both have similar patterns and, as early as the fifties, studies were conducted in rats to identify the effects of thyroid hormones on the brain development (9). Conditions observed in humans have been duplicated at various stages by using synthetic antithyroid drugs or ablative radioactive iodine. While working on the hippocampus of rat pups (10), Goodman and Gilbert observed the presence of a heterotopia at the bottom of the corpus callosum, on each side of the third ventricle, when the dams were given propylthiouracil or methimazole (1). This heterotopia was mostly comprised of neuronal cells born between 17 and 19 d after conception and was detected as early as 3 d after birth. In rats, the last third of gestation corresponds to a period of intense neuronal genesis and migration. In humans, the described phenomenon would probably find its roots between the end of the first and the middle of the second trimester of pregnancy. In fact, these two periods precede the onset of a significant fetal thyroid function in both species (11). Goodman and Gilbert’s results, therefore, suggest that maternal thyroxin supply allows for the proper targeting of a population of neuronal cells that would normally move to the bottom of the corpus callosum after embryonic d 17–19 in rats.
What stakes are rising from this observation? First, it is intriguing why such heterotopia had not been described before. If the strain (Long-Evans) of animals played any role, it would point at genetic factors that are as of yet undetermined. It also gives us a new model to study the mechanisms by which the thyroid system acts on neural development. Not long ago, Munoz and colleagues (12) showed that thyroid hormones regulate reelin expression. Reelin is involved in the migration of certain types of neuronal cells (e.g. Cajal-Retzius cells in layer I of the cortex), before they reach their final location in neocortical, subcortical (hippocampus) and cerebellar (granules layer) structures where they fully differentiate. It is likely that other factors are involved in the neuronal migration processes affected by a lack of thyroid hormones and that several have yet to be identified, if not many. Given the timing, the heterotopia could be composed of neuronal cells initially headed for the cortical layers II–IV. It is, however, not known whether the heterotopic cells, or their precursors, specifically expressed thyroid hormone receptors and were direct targets of propylthiouracil-induced hypothyroidism.
In fact, the thyroid and central nervous systems are tightly intertwined. Several factors are involved in modulating or mediating the thyroid hormone effects on the brain. These include the level of expression of thyroid hormone receptor(s), mostly 
isoforms (13), but also types II and III iodothyronine deiodinases (14) and thyroid hormone transporters (5). Other thyroid hormone binding proteins (15) and the TSH receptor (16) may have their part as well. One mechanism proposed by the authors to explain migration impairment relies on the work of Ruiz-Marcos and colleagues (17), who showed that hypothyroidism alters the radial glia that, in fact, was observed at later stages of development. Another observation made 25 yr ago presents striking similarities to that of Goodman and Gilbert. In mice, glial fibrillary acidic protein-negative cells migrate between embryonic d 15 and 17 from the lateral ventricular zone to underlie the developing corpus callosum (18). Initially improperly named the glial sling, this population of migratory neuronal cells has also been found during human brain development (19). These cells express GAP-43, a factor that regulates the growth state of axon terminals. GAP-43 is differentially regulated in various brain areas upon induction of hypothyroidism, T3 treatment, or abrogation of TR expression in mice (13).
Myriad neurological disorders have been described, the mechanisms of which are still poorly or incompletely understood. One challenge will be to identify whether and how the thyroid system regulate their occurrence or severity. Because they are preventable, the deleterious effects caused by a mild a reduction of thyroid hormone levels during pregnancy need to be more comprehensively characterized. It will be important to determine how the interplay between hypothyroidism and associated risk factors impacts the functional outcome for the patient.
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Received March 7, 2007.
Accepted for publication March 9, 2007.
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References |
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 Top References |
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. Behav Brain Res 177:109–116[CrossRef][Medline]
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