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Thyroid hormone effects on Krox-24 transcription in the post-natal mouse brain are developmentally regulated but are not correlated with mitosis

Abstract

Krox-24 (NGFI-A, Egr-1) is an immediate-early gene encoding a zinc finger transcription factor. As Krox-24 is expressed in brain areas showing post-natal neurogenesis during a thyroid hormone (T3)-sensitive period, we followed T3 effects on Krox-24 expression in newborn mice. We analysed whether regulation was associated with changes in mitotic activity in the subventricular zone and the cerebellum. In vivo T3-dependent Krox-24 transcription was studied by polyethylenimine-based gene transfer. T3 increased transcription from the Krox-24 promoter in both areas studied at post-natal day 2, but was without effect at day 6. An intact thyroid hormone response element (TRE) in the Krox-24 promoter was necessary for these inductions. These stage-dependent effects were also seen in endogenous Krox-24 mRNA levels: activation at day 2 and no effect at day 6. Moreover, similar results were obtained by examining β-galactosidase expression in heterozygous mice in which one allele of the Krox-24 gene was disrupted with an in-frame Lac-Z insertion. However, bromodeoxyuridine incorporation showed mitosis to continue through to day 6. We conclude first, that T3 activates Krox-24 transcription during early post-natal mitosis but that this effect is extinguished as development proceeds and second, loss of T3-dependent Krox-24 expression is not correlated with loss of mitotic activity.

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Acknowledgements

We are greatly indebted to Dr P Charnay (INSERM, ENS, Paris) for his generous gift of Krox-24+/− mutant mice. We thank the Association pour la Recherche contre le Cancer (ARC), the Association Française contre les Myopathies (AFM), the Association pour la Recherche sur la Sclerose en Plaque (ARSEP) and AIRC for financial support. MTG was a recipient of predoctoral scholarships from ARC, Ligue Contre le Cancer and the FRM.

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Ghorbel, M., Seugnet, I., Hadj-Sahraoui, N. et al. Thyroid hormone effects on Krox-24 transcription in the post-natal mouse brain are developmentally regulated but are not correlated with mitosis. Oncogene 18, 917–924 (1999). https://doi.org/10.1038/sj.onc.1202378

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