title: Prenatal exposure to suberoylanilide hydroxamic acid perturbs corticogenesis.
abstract: 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.
authors.affiliation: Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan; Laboratory of Pharmacology and Toxicology, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada (UGM), Yogyakarta, Indonesia.
authors.forename: Nunung
authors.initials: N
authors.lastname: Yuniarti
authors.forename: Berry
authors.initials: B
authors.lastname: Juliandi
authors.forename: Chai
authors.initials: C
authors.lastname: MuhChyi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sanosaka
authors.forename: Kinichi
authors.initials: K
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D011247:Pregnancy; D020825:T-Box Domain Proteins / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; D000077337:Vorinostat; C491198:Eomes protein, mouse; C486336:Neurog1 protein, mouse
keywords: Corticogenesis; HDAC inhibitor; Histone acetylation; Neural stem cells; Neurogenesis; SAHA