232 2 J BERNAL Thyroid hormones and cortex 232:2 R83–R97 Review development Thyroid hormone regulated genes in cerebral cortex development Juan Bernal Correspondence Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas y Universidad should be addressed Autónoma de Madrid, and Center for Biomedical Research on Rare Diseases, Instituto de Salud Carlos to J Bernal III, Madrid, Spain Email [email protected] Abstract The physiological and developmental effects of thyroid hormones are mainly due to Key Words the control of gene expression after interaction of T3 with the nuclear receptors. To f brain understand the role of thyroid hormones on cerebral cortex development, knowledge f development of the genes regulated by T3 during specific stages of development is required. In our f fetus laboratory, we previously identified genes regulated by 3T in primary cerebrocortical f gene expression cells in culture. By comparing these data with transcriptomics of purified cell types from f thyroid hormone the developing cortex, the cellular targets of T3 can be identified. In addition, many of metabolism the genes regulated transcriptionally by T3 have defined roles in cortex development, from which the role of T3 can be derived. This review analyzes the specific roles of Endocrinology T -regulated genes in the different stages of cortex development within the of 3 physiological frame of the developmental changes of thyroid hormones and receptor concentrations in the human cerebral cortex during fetal development. These data Journal indicate an increase in the sensitivity to T3 during the second trimester of fetal development. The main cellular targets of T3 appear to be the Cajal-Retzius and the subplate neurons. On the other hand, T3 regulates transcriptionally genes encoding extracellular matrix proteins, involved in cell migration and the control of diverse signaling pathways. Journal of Endocrinology (2017) 232, R83–R97 Introduction The actions of thyroid hormones (TH) on brain develop­ deficiency. Several reviews have appeared recently ment and function are among the more relevant of describing in detail the pathophysiology of these these hormones, strongly influencing neuromotor conditions (Refetoff & Dumitrescu 2007, Kurian & performance, cognition and mood. Multiple conditions Jungbluth 2014, Bell et al. 2016, Moleti et al. 2016, van cause impaired TH action during brain development. Gucht et al. 2016). In the present article, I will try to These include iodine deficiency, maternal and fetal integrate recent information on genomic mechanisms hypothyroidism, maternal hypothyroxinemia, of action of TH on cerebral cortex development within prematurity, nuclear T3 receptor mutations (TR) and the physiological frame of thyroid homeostasis during mutations of the monocarboxylate 8 transporter fetal development. First, I will summarize the main (MCT8) gene SLC16A2. These conditions may lead to features of TH homeostasis in the brain during human various degrees of mental retardation and neurological fetal stages, as the context in which cerebral maturation impairment, which are particularly severe in MCT8 takes place. Then, I will use current concepts on cerebral http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0424 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 05:24:04AM via free access 10.1530/JOE-16-0424 Review J BERNAL Thyroid hormones and cortex 232:2 R84 development cortex development at the cellular and molecular levels as the frame to identify possible roles of T3 on these processes. To accomplish this, I will use recent data from our laboratory on T3­regulated genes (Gil­Ibanez et al. 2015), many of which control key processes in cortex development. I believe that the integration of all the information will allow formulating coherent hypothesis on the general role and specific actions of TH on cortex development. The context: fetal thyroid hormone homeostasis Thyroid hormone concentrations in fetal fluids The main features of thyroid hormone homeostasis in the human fetus are represented in Fig. 1. The figure represents data on TH concentrations in fetal fluids and in the developing cerebral cortex, as well as the concentrations of the nuclear T3 receptor protein in the whole brain, during fetal development from the 6th to the 36th postmenstrual weeks (PMW). The date at which the fetal thyroid gland starts functioning is marked by a shaded vertical box between the 10th and the 12th PMW (Shepard 1967, Burrow et al. 1994). Endocrinology of During the first trimester, 4T and T3 are present in Figure 1 the coelomic fluid, an ultrafiltrate of the maternal serum Thyroid hormone and TH receptor concentrations in the human fetus. (Calvo et al. 2002). T4 in the coelomic fluid is derived from This figure contains replotted data on the concentrations of TH in Journal coelomic and amniotic fluids (Burrow et al. 1994, Calvo et al. 2002), fetal the maternal pool, and T4 concentrations in coelomic serum (Thorpe-Beeston et al. 1991) and cerebral cortex (Kester et al. fluid and maternal serum are positively correlated. The 2004) as a function of fetal age expressed in postmenstrual weeks. The total T4 (TT4) concentration (1–2 nM) is about 100 times lower part of the figure shows the number of 3T receptor molecules per less than the maternal concentration, although the nucleus recalculated from the original publication (Bernal & Pekonen 1984) assuming 8 pg DNA/nucleus. The inset shows the relative affinity of free fraction is much higher. In the amniotic fluid, TT4 the human fetal receptor for triac (T3A), T3, T4, rT3 (Bernal & Pekonen concentration is very low (0.1 nM) before the 12th week 1984). The shaded bar marks the date at which the fetal thyroid gland and increases to 2 nM after the 12th week and 4 nM at the concentrates iodine and contains thyroglobulin and iodinated compounds (Shepard 1967). end of gestation (Burrow et al. 1994, Calvo et al. 2002). The data on T and T concentrations in the fetal serum 4 3 TH transport to the brain represented in Fig. 1 are taken from Thorpe­Beeston and coworkers (Thorpe­Beeston et al. 1991, Thorpe­Beeston & Thyroid hormones are amphipathic molecules, i.e., Nicolaides 1993) and extend from the 12th to the 36th contain polar residues soluble in water and non­polar PMW. Serum TT4 concentration increases from around residues soluble in lipids. At the physiological pH, they 26 nM at 12 weeks to 100–140 nM at 36 weeks, reaching are present in body fluids mainly in the zwitter ionic form − + maternal concentrations. Free T4 (FT4) increases from (the amino acid side chain is in the form of –COO –NH3 ) about 1–2 pM at 12 weeks to 25 pM at the end of gestation (Toth et al. 2013) making it difficult to diffuse through (Thorpe­Beeston et al. 1991, Guibourdenche et al. 2001) the membranes, which are essentially impermeable to and TT3 from the almost undetectable level of 0.1 nM at ions. Diffusion of TH through the cellular membranes is 12 weeks to 1 nM at 36 weeks. In contrast to T4, T3 levels facilitated by membrane transporters acting on the influx at the end of gestation do not reach the maternal levels, and efflux to and from the cell interior, depending on most probably reflecting the immaturity of the 4T to T3 the relative free hormone concentrations at either side conversion process. of the membrane. Passage to the brain requires crossing http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0424 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 05:24:04AM via free access Review J BERNAL Thyroid hormones and cortex 232:2 R85 development the blood–brain barrier (BBB). The BBB is formed by the endothelial cells of brain capillaries joined together strongly by tight junctions (Abbott et al. 2010), severely restricting paracellular transport, and access to the brain requires crossing the luminal and abluminal membranes of the endothelial cells. The need of TH for specific transporters is now firmly established after the finding that mutations of the SLC16A2 gene, encoding MCT8 lead to extremely severe neurological impairment and intellectual deficiency (Lopez­Espindola et al. 2014, Bernal et al. 2015). Many transporter proteins have the capacity of TH transport, but two of them are the most Figure 2 relevant for BBB transport: MCT8 with affinity for T4 and Model of TH transport and action in the brain. TH crosses the BBB T3, and the organic anion transporter polypeptide 1C1 through MCT8 and OATP1C1. MCT8 transports T4 and T3, whereas (OATP1C1, encoded by the SLCO1C1 gene) with much OATP1C1 is more specific for 4T . MCT8 and OATP1C1 are expressed in the endothelial microvascular cells and in the membrane of astrocytes and higher selectivity for T4. These are integral membrane neurons. OATP1C1 is present in the astrocytic end feet in contact with the proteins consisting of 12 transmembrane domains endothelial cells, so that transport of T4 to the astrocytes is facilitated by expressed in neural cells and in the BBB. They are also OATP1C1. In the astrocytes, T4 is converted to T3. The T3 formed has present in the endothelial cells of the choroid plexus. action on the astrocytes and also on neurons after crossing the cell membranes. This last step is not strictly dependent on MCT8 as it can It is reasonable to assume that the major route of TH to occur in its absence. The location of other secondary transporters for TH the brain is the BBB as its exchange surface is about 5000 is shown, but their specific role has not been defined. The neurons have DIO3 activity that converts T and T to rT and T , respectively. fold that of choroid plexus (Pardridge 1983). Transport 4 3 3 2 through the choroid plexus may be more relevant at early stages of development, for example, during the formation (MCT8) and Slco1c1 (OATP1C1) genes in mice induces cerebral hypothyroidism (Mayerl et al.