Involvement of T3R alpha- and beta-receptor subtypes in mediation of T3 functions during postnatal murine intestinal development

Background & Aims: Thyroid hormones are implicated in intestinal developmen t. Their effects are mediated by nuclear receptors, which are transcription al regulators activated upon binding of triiodothyronine. The aim of this s tudy was to define the involvement of the receptor subtypes during intestin al development. Methods: We used strains of knockout mice lacking T3R alpha , T3R beta, or both receptors, encoded by T3R alpha and T3R beta genes. Res ults: Morphological features and expression of digestive enzymes and of two intestinal regulators, Cdx-1 and Cdx-2, were compared in wildtype and T3R alpha, T3R beta, and T3R alpha beta knockout animals. T3R alpha-/- mice had abnormal intestinal morphology, assessed by a decrease in the number of ep ithelial cells along the crypt-villus axis and a decrease in proliferating crypt cells. Expression of Cdx-1 and Cdx-2, and of the digestive enzymes, w as down-regulated. These parameters can be partially reversed by T3 injecti on. A similar (jejunum) or more severe (ileum) phenotype was found in T3R a lpha beta double mutants. In contrast, no changes occurred in T3R beta mice . Conclusions: These data describe for the first time a direct effect of TH through the T3R alpha-receptor subtypes on postnatal intestinal mucosa mat uration. They also suggest that T3R beta receptors are dispensable but can partially substitute for T3R alpha.