The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia - defined as thyroxine (T4) concentrations that are low for the stage of pregnancy - is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine-placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible.

Most mammals have two types of cone photoreceptors, which contain either medium wavelength (M) or short wavelength (S) opsin. The number and spatial organization of cone types varies dramatically among species, presumably to fine-tune the retina for different visual environments. In the mouse, S-and M-opsin are expressed in an opposing dorsal-ventral gradient. We previously reported that cone opsin patterning requires thyroid hormone ␤2, a nuclear hormone receptor that regulates transcription in conjunction with its ligand, thyroid hormone (TH). Here we show that exogenous TH inhibits S-opsin expression, but activates M-opsin expression. Binding of endogenous TH to TR␤2 is required to inhibit S-opsin and to activate M-opsin. TH is symmetrically distributed in the retina at birth as S-opsin expression begins, but becomes elevated in the dorsal retina at the time of M-opsin onset (postnatal day 10). Our results show that TH is a critical regulator of both S-opsin and M-opsin, and suggest that a TH gradient may play a role in establishing the gradient of M-opsin. These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development.photoreceptor ͉ retinal development ͉ nuclear hormone receptor T hyroid hormone (TH) is secreted mostly as thyroxine (T4) from the thyroid gland and converted locally to a transcriptionally active form, 3,5,3Ј-triiodothyronine (T3), by iodothyronine deiodinating enzymes (1). T3 receptors bind to DNA regulatory elements, often as heterodimers with retinoid X receptors (RXRs), to activate or repress transcription of target genes (for review, see refs. 2 and 3). T3 regulates diverse developmental processes in multiple regions of the central nervous system including the hippocampus, cerebral cortex, inner ear, and cerebellum (4-8). Numerous developmental processes are TH-dependent, including cell differentiation, migration, and dendritic growth (2, 3, 9-11). Perturbations in maternal or fetal TH in humans can lead to clinical syndromes ranging from severe mental retardation and hearing loss to mild or moderate deficits in motor skills, language, memory, and attention (12)(13)(14).In the retina, the TH ␤2 receptor isoform (TR␤2) is restricted to cone photoreceptors (15, 16), and we previously showed that it is a critical regulator of late-stage cone differentiation. In the first stage of cone differentiation, cones exit the cell cycle and begin to express specific transcription factors, including cone rod homeobox (CRX), TR␤2,. In the second stage of differentiation, cones express opsin and form specific synaptic connections. Most mammalian cones express short wavelength (S-opsin) or medium wavelength (M-opsin) opsin. However, the spatial arrangement of cone types varies considerably among species. In mice, S-opsin expression begins just before birth and is expressed predominantly in ventral cones. By contrast, M-opsin expression begins at the end of the first postnatal week and is expressed predominantly in dorsal cones (21, 22...