Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue Transducin-like-Enhancer of split 1 in postmitotic neurons

Abstract

Transducin-like Enhancer of split (TLE) 1 is a mammalian transcriptional corepressor homologous to Drosophila Groucho. In Drosophila, Groucho acts together with bHLH proteins of the Hairy/Enhancer of split (HES) family to negatively regulate neuronal differentiation. Loss of the functions of Groucho or HES proteins results in supernumerary central and peripheral neurons. This suggests that mammalian TLE/Groucho family members may also be involved in the regulation of neuronal differentiation. Consistent with this possibility, TLE1 is expressed in proliferating neural progenitor cells of the central nervous system, but its expression is transiently down-regulated in newly generated postmitotic neurons. Based on these observations, we investigated whether persistent TLE1 expression in postmitotic neurons would perturb the normal course of neuronal development. Transgenic mice were derived in which the human TLE1 gene is regulated by the promoter of the Tα1 α-tubulin gene, which is exclusively expressed in postmitotic neurons. In these mice, constitutive expression of TLE1 inhibits neuronal development in the embryonic forebrain leading to increased apoptosis and neuronal loss in the ventral and dorsal telencephalon. These results provide the first direct evidence that TLE1 is an important negative regulator of postmitotic neuronal differentiation in the mammalian central nervous system.