Valproic acid-induced changes in gene expression during neurulation in a mouse model

Abstract

The teratogenic potential of valproic acid has been well established both in experimental models and in human clinical studies. As with all human teratogens, there are genetically determined differences in individual susceptibility to the induction of congenital defects. Using a mouse model of valproate‐induced neural tube defects, a study was undertaken to examine differential changes in gene expression for selected transcription factor (Pax‐3, Emx‐1, Emx‐2, c‐fos, c‐jun, creb) and cell cycle checkpoint genes (bcl‐2, p53, wee‐1) during neural tube closure. In general, exposure to teratogenic concentrations of valproic acid elicited GD 9:12 control levels of transcription factor mRNA expression in GD 9:0 embryos of both strains. This accelerated developmental profile is marked by significant elevation of Emx‐1, Emx‐2, c‐fos, c‐jun, and creb expression. There was also a significant overexpression of the cell cycle genes p53 and bcl‐2 in the LM/Bc embryos in response to the teratogenic insult. Examination of the ratio of expression of these genes clearly favored bcl‐2, which supports the hypothesis that altered neuroepithelial cell proliferation rates, rather than increased apoptosis, is the underlying mechanism by which valproic acid alters normal neural tube morphogenesis. An investigation into interactive effects of these genes on the molecular profile of GD 9:0 embryos further validated this observation. That is, the overall proliferative state among the control embryos was prematurely modified into a more differentiated state following teratogenic insult. These results suggest that alterations in the expression of multiple genes are most likely responsible for valproic acid‐induced neural tube defects. Teratology 54:284–297, 1996. © 1997 Wiley‐Liss, Inc.

Experimental studies on cervical and lumbar ribs in mouse embryos

“…1991;Kessel 1992;Linney 1992;Marshall et al . 1996;Padmanabhan & Ahmed 1996, 1997Wlodarczyk et al . 1996).…”

“…The kind of developmental stage-dependent susceptibility of the skeletal system reported here and elsewhere in rats and mice in response to VPA treatment (Padmanabhan & Hameed 1994;Menegola et al 1996;Padmanabhan & Ahmed 1997) are said to be related to the ability of VPA to alter expression of developmental genes (Finnell et al 1997) such as Hox 3.1,wee 1, Pax-3, Emx-1, Emx-2, c-fos, c-jun, creb and cell cycle checkpoint genes bcl-2, p53; folate binding proteins (Menegola et al 1996;Wlodarczyk et al 1996;Finnell et al 1997;Barber et al 1999;Bennett et al 2000). Both VPA and RA produce similar morphological alterations in the axial region, including changes in the neural tube of rat embryos (Seegmiller et al 1991).…”

The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy

“…Adding to the complexity of regulatory changes in SMN gene expression, recent studies also indicate increased DNA binding activity of the transcription factors AP1 and Sp1 to their respective binding sites in the SMN promoter (Fig. 2) after exposure to the HDAC inhibitor VPA (Brichta et al 2003;Wlodarczyk et al 1996;Arinze and Kawai 2003). Moreover, several HDACIs have been shown to increase the FL-SMN2 transcript stronger than the SMND7 transcript, significantly shifting SMN2 splicing towards FL-SMN (Andreassi et al 2004;Brichta et al 2003;Chang et al 2001;Hahnen et al 2006;Riessland et al 2006;Sumner et al 2003).…”

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

“…Moreover, the assessment of valproic acid revealed specific effects on transcription factors like Pax-3, Emx-1, Emx-2 and on cell cycle checkpoint genes like bel-2 and p53 as well as on growth factor genes. All of them are involved in the regulation of neural tube closure as shown in different studies using these techniques [142,143].…”