Research Report T3 differentially regulates TRH expression in developing hypothalamic neurons in vitro Alfonso Carreón-Rodríguez, Jean-Louis Charli, Leonor Pérez-Martínez ⁎ Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, UNAM, A.P. 510-3, Cuernavaca, Morelos 62271, Mexico ARTICLE INFO ABSTRACT Article history: Accepted 11 September 2009 Available online 18 September 2009 Triiodothyronine (T3) plays an important role during development of the central nervous system. T3 effects on gene expression are determined in part by the type of thyroid hormone receptors (TRs) expressed in a given cell type. Previous studies have demonstrated that thyrotropin releasing hormone (TRH) transcription in the adult hypothalamus is subjected to negative regulation by thyroid hormones. However, the role of T3 on the development of TRH expression is unknown. In this study we used primary cultures derived from 17-day-old fetal rat hypothalamus to analyze the effects of T3 on TRH gene expression during development. T3 increased TRH mRNA expression in immature cultures, but decreased it in mature cultures. In addition, T3 up-regulated TRα1 and TRβ2 mRNA expression. TRα1 expression coincided chronologically with that of TRH in the rat hypothalamus in vivo. Maturation of TRH expression in the hypothalamus may involve T3 acting through TRα1. © 2009 Elsevier B.V. All rights reserved. Keywords: Development Neuronal differentiation TRH Hypothalamus Gene expression 1. Introduction Thyroid hormones (TH) are secreted mostly as thyroxine (T4) from the thyroid gland and converted in diverse tissues to the transcriptionally active form 3,5,3′-triiodothyronine (T3), by the deiodinases type 1 and 2 (D1, D2) (Yen, 2001). T3 plays a key role during central nervous system (CNS) development. Deficiency during the fetal and early postnatal period leads to striking abnormalities in dendritic and axonal growth, synaptogenesis, neuronal migration, myelination as well as neuronal cell death (Chan and Kilby, 2000). T3 treatment immediately after birth is sufficient to prevent most of the brain damage induced by neonatal hypothyroidism; such treatment however cannot fully rescue abnormal brain development induced by hypothyroidism in utero (i.e., by maternal iodine deficiency) (Koibuchi and Iwasaki, 2006). Thus, T3 must act within a critical developmental window beyond which hormone replacement cannot recover normal function, as observed for cerebellum (Koibuchi et al., 2003) or cochlea (Karolyi et al., 2007) development. During neurodevelopment, activation and repression of specific genes are critical to complete the neuronal differ- entiation program. T3 mediates positive and negative gene expression through nuclear TRs. Two TRs (α and β) have been identified; they give rise to different splice variants. The TRα gene encodes five protein products (TRα1, TRα2, TRα3, and the truncated products ΔTRα1 and ΔTRα2) of which only TRα1 binds T3. The TRβ gene encodes four products (TRβ1, TRβ2, TRβ3 and truncated ΔTRβ3) that bind T3, but the truncated isoform does not bind DNA. There is no clear physiological role for the non-receptor proteins (Zhang and Lazar, 2000, Santisteban and Bernal, 2005). However, some non-genomic actions of thyroid hormones have been attributed to the truncated TR isoforms and also to the plasma membrane receptor, integrin ανβ3 (Davis et al., 2008). BRAIN RESEARCH 1305 (2009) 20 – 30 ⁎ Corresponding author. Fax: +52 777 3291622. E-mail address: leonor@ibt.unam.mx (L. Pérez-Martínez). 0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2009.09.042 available at www.sciencedirect.com www.elsevier.com/locate/brainres