Jiang Boran, Kumar S Dinesh, Loh Wan Ting, Manikandan J, Ling Eng-Ang, Tay Samuel S W, Dheen S Thameem
Molecular Neurobiology Laboratory, Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
J Neurosci Res. 2008 Dec;86(16):3481-93. doi: 10.1002/jnr.21800.
Maternal diabetes causes congenital malformations in various organs including the neural tube in fetuses. In this study, we have analyzed the differential gene expression profiling in the cranial neural tube of embryos from diabetic and control mice by using the oligonucleotide microarray. Expression patterns of genes and proteins that are differentially expressed in the cranial neural tube were further examined by the real-time reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry. Proliferation index and apoptosis were examined by BrdU (5-bromo-2-deoxyuridine) labeling and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay, respectively. Embryos (E11.5) of diabetic pregnancies displayed distortion in neuroepithelia of the cranial neural tube. Microarray analysis revealed that a total of 390 genes exhibited more than twofold changes in expression level in the cranial neural tube of embryos from diabetic mice. Several genes involving apoptosis, proliferation, migration, and differentiation of neurons in the cranial neural tube were differentially expressed in embryos of diabetic pregnancy. In addition, maternal diabetes perturbed the development of choroid plexus and ventricular systems and reduced the production of proteins such as Ttr and Igf2 in the developing brain, indicating that these changes could impair the survival and proliferation of neuroepithelial cells and neurogenesis in embryos of diabetic mice. It is concluded that altered expression of a variety of genes involved in brain development is associated with cranial neural tube dysmorphogenesis that may subsequently contribute to intellectual impairment of the offspring of a diabetic mother.
母体糖尿病会导致胎儿包括神经管在内的各种器官出现先天性畸形。在本研究中，我们使用寡核苷酸微阵列分析了糖尿病小鼠和对照小鼠胚胎颅神经管中的差异基因表达谱。通过实时逆转录聚合酶链反应、原位杂交和免疫组织化学进一步检测了在颅神经管中差异表达的基因和蛋白质的表达模式。分别通过BrdU（5-溴-2-脱氧尿苷）标记和TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）测定法检测增殖指数和细胞凋亡。糖尿病妊娠的胚胎（E11.5）在颅神经管的神经上皮中表现出畸形。微阵列分析显示，共有390个基因在糖尿病小鼠胚胎的颅神经管中表达水平有两倍以上的变化。在糖尿病妊娠的胚胎中，涉及颅神经管中神经元凋亡、增殖、迁移和分化的几个基因存在差异表达。此外，母体糖尿病扰乱了脉络丛和脑室系统的发育，并减少了发育中大脑中Ttr和Igf2等蛋白质的产生，表明这些变化可能损害糖尿病小鼠胚胎中神经上皮细胞的存活和增殖以及神经发生。结论是，参与大脑发育的多种基因表达改变与颅神经管畸形发生有关，这可能随后导致糖尿病母亲后代的智力障碍。
