Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos

IF 1.3 4区 医学 Q3 PEDIATRICS Congenital Anomalies Pub Date : 2024-02-25 DOI:10.1111/cga.12553
Reiko Suzuki, Hajime Imai
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Abstract

Cranial neural crest cells (NCCs) are critical for craniofacial development. The administration of valproic acid (VPA) to pregnant females causes craniofacial malformations in offspring. However, the in vivo influence of VPA on mammalian cranial NCCs remains unclear. In this study, we aimed to elucidate the developmental stage-specific effect of VPA on cranial NCCs through the administration of a single dose of VPA to pregnant rat females immediately prior to the formation of the cranial neural crest (NC). We performed whole-mount immunohistochemistry or in situ hybridization to examine localization changes of gene transcripts associated with the epithelial–mesenchymal transition of the cranial NC (i.e., cranial NCC formation) and cranial NCC migration. The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA expression was decreased in the midbrain–rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch (BA) 1, through VPA administration, thus reducing the formation of SNAI2-positive NCCs. Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration. In vitro verification experiments using the whole embryo culture system revealed that midbrain–R4 NCC migration was abnormal. These results indicate that VPA reduces the formation/delamination of the midbrain–R1/2 NCCs in a developmental stage-specific manner and subsequently causes the abnormal migration of R4 NCCs, which suggests that the abnormal formation and migration of cranial NCCs contribute to the inhibition of axonal elongation in the trigeminal nerve and a reduction in head size.

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丙戊酸对大鼠胚胎早期发育阶段颅神经嵴细胞的形成和迁移的影响
颅神经嵴细胞(NCC)对颅面部的发育至关重要。孕妇服用丙戊酸(VPA)会导致后代颅面畸形。然而,VPA 对哺乳动物颅骨 NCC 的体内影响仍不清楚。在本研究中,我们旨在通过在妊娠大鼠头颅神经嵴(NC)形成前给其注射单剂量 VPA,来阐明 VPA 对头颅 NCC 的发育阶段特异性影响。我们采用整装免疫组化或原位杂交技术检测了与颅神经嵴上皮-间质转化(即颅神经嵴形成)和颅神经嵴迁移相关的基因转录本的定位变化。结果表明,在中脑-虹膜(R)1/2 NC中,Hoxa2 mRNA被异常检测到,Sox9 mRNA表达减少,而中脑-虹膜(R)1/2 NC形成的颅骨NCC会通过VPA施用迁移到额骨团(FNM)和分支弓(BA)1,从而减少了SNAI2阳性NCC的形成。在 BA2 中正常检测到 Hoxa2 阳性的 NCC,而在 FNM 和 BA1 中则异常检测到 Hoxa2 阳性的 NCC。使用全胚胎培养系统进行的体外验证实验显示,中脑-R4 NCC迁移异常。这些结果表明,VPA 以发育阶段特异性的方式减少了中脑-R1/2 NCC 的形成/分层,随后导致 R4 NCC 的异常迁移,这表明头颅 NCC 的异常形成和迁移导致了三叉神经轴突延伸的抑制和头部尺寸的缩小。
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来源期刊
Congenital Anomalies
Congenital Anomalies PEDIATRICS-
自引率
0.00%
发文量
49
审稿时长
>12 weeks
期刊介绍: Congenital Anomalies is the official English language journal of the Japanese Teratology Society, and publishes original articles in laboratory as well as clinical research in all areas of abnormal development and related fields, from all over the world. Although contributions by members of the teratology societies affiliated with The International Federation of Teratology Societies are given priority, contributions from non-members are welcomed.
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