Prenatal exposure to suberoylanilide hydroxamic acid perturbs corticogenesis

• Published in: Neuroscience research Vol. 77; no. 1-2; pp. 42 - 49
• Main Authors: Yuniarti, Nunung, Juliandi, Berry, MuhChyi, Chai, Noguchi, Hirofumi, Sanosaka, Tsukasa, Nakashima, Kinichi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.09.2013
• Subjects: Animals; Antineoplastic Agents - pharmacology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - embryology; Corticogenesis; Female; HDAC inhibitor; Histone acetylation; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; Hydroxamic Acids - pharmacology; Maternal Exposure; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - metabolism; Neural stem cells; Neurogenesis; Neurogenesis - drug effects; Pregnancy; SAHA; T-Box Domain Proteins - metabolism; HDAC inhibitor; SAHA; Neural stem cells; Histone acetylation; Corticogenesis; Neurogenesis
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2013.06.004

•Prenatal SAHA exposure enhances embryonic cortical neurogenesis.•SAHA promotes indirect neurogenesis of NS/PCs in the embryonic forebrain.•Prenatal SAHA exposure perturbs cortical lamination of neonatal cortex.•SAHA promotes the production of upper-cortical layer neurons. Suberoylanilide hydroxamic acid (SAHA) is one of the epidrugs developed for cancer treatment that works epigenetically by inhibiting histone deacetylases (HDACs). SAHA has been reported to diffuse across the placenta and found in fetal plasma in preclinical study, implying that it can influence fetus if taken by pregnant cancer patients. However, report regarding this aspect and the study of in utero HDAC inhibition by SAHA especially on fate specification of neural stem/progenitor cells within the developing mammalian cortex, is yet unavailable. Here we show that transient exposure of SAHA to mouse embryos during prominent neurogenic period resulted in an enhancement of cortical neurogenesis, which is accompanied by an increased expression of proneuronal transcription factor Neurog1. Neurogenesis was enhanced due to the increase number of proliferating Tbr2+ intermediate progenitor cells following SAHA exposure. In this relation, we observed that SAHA perturbed neonatal cortical lamination because of the increased production of Cux1+ and Satb2+ upper-layer neurons, and decreased that of Ctip2+ deep-layer neurons. Furthermore, an upper-layer neuronal lineage determinant Satb2 was also up-regulated, whereas those of deep-layer ones Fezf2 and Ctip2 were down-regulated by SAHA treatment. Taken together, our study suggests that proper regulation of HDACs is important for precise embryonic corticogenesis.