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Identification of early-responsive genes correlated to valproic acid-induced neural tube defects in mice
Akinobu Okada1, Kiyoshi Kushima, Yoshinobu Aoki
1Drug Safety Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
Background:
Valproic acid (VPA) causes the failure of neural tube closure in newborn mice. However, the molecular mechanism of its teratogenesis is unknown. This study was conducted to investigate the genomewide effects of VPA disruption of normal neural tube development in mice.
Methods:
Microarray analysis was performed on the head part of NMRI mouse embryos treated for 1 hr with VPA on gestational day (GD) 8. Subsequently, we attempted to isolate genes that changed in correlation with the teratogenic action of VPA by employing reduced teratogenic VPA analogs, valpromide (VPD) and valnoctamide (VCD), in a real-time PCR study.
Results:
Microarray results demonstrated that during neurulation, many genes, some of whose functions are known and some unknown, were either increased or decreased after VPA injection. Some genes were affected by VPD or VCD in the same way as VPA, but others were not changed by the analogs. In this way, our system identified 11 increased and 20 decreased genes. Annotation analysis revealed that the increased genes included gadd45b, ier5, per1, phfl3, pou3f1, and sox4, and the decreased genes included ccne2, ccnl, gas5, egr2, sirt1, and zfp105.
Conclusions:
These findings demonstrate that expression changes in genes having roles in the cell cycle and apoptosis pathways of neural tube cells were strongly expected to relate to the teratogenic, but not antiepileptic, activity of VPA. Our approach has allowed the expansion of the catalog of molecules immediately affected by VPA in the developing neural tube.
Insights
Valproic acid (VPA) disrupts neural tube development by altering gene expression in mouse embryos. These changes in cell cycle and apoptosis genes are linked to VPA's teratogenic effects.
Area of Science:
- Developmental Biology
- Genomics
- Toxicology
Background:
- Valproic acid (VPA) is known to cause neural tube defects in newborns.
- The precise molecular mechanisms underlying VPA-induced teratogenesis remain unclear.
- This study investigates the genome-wide impact of VPA on neural tube development.
Purpose of the Study:
- To identify genes affected by VPA during mouse neural tube development.
- To elucidate the molecular pathways involved in VPA teratogenesis.
- To differentiate teratogenic from anticonvulsant effects of VPA.
Main Methods:
- Microarray analysis of mouse embryos (NMRI) treated with VPA on gestational day 8.
- Utilized VPA analogs, valpromide (VPD) and valnoctamide (VCD), to correlate gene changes with teratogenic action.
- Real-time PCR was employed to validate gene expression alterations.
Main Results:
- VPA treatment significantly altered the expression of numerous genes during neurulation.
- Microarray analysis identified 11 upregulated and 20 downregulated genes.
- Specific genes like gadd45b, sox4, ccne2, and sirt1 showed altered expression patterns.
Conclusions:
- Gene expression changes in cell cycle and apoptosis pathways are implicated in VPA's teratogenic effects.
- The identified molecular targets are specifically related to teratogenesis, not VPA's antiepileptic activity.
- This research expands the understanding of molecules directly impacted by VPA during embryonic development.
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