Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Foot and Ankle Surgery Center of Shandong University and Department of Hand and Foot Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China.
Cell Death Dis. 2019 Mar 1;10(3):211. doi: 10.1038/s41419-019-1438-z.
Offspring of mothers with hyperglycemia during pregnancy have a higher incidence of long-term neuropsychiatric disorders than offspring from a normal pregnancy, indicating that neocortical neurogenesis might be affected by maternal hyperglycemia. A paucity of study evaluating the effects of hyperglycemia on neocortical neurogenetic differentiation of neural stem cells, and the mechanism remains unclear. We sought to investigate the the roles and possible molecular mechanism of maternal hyperglycemia on neocortical neurogenetic differentiation of neural stem cells. We established a mouse model of a hyperglycemic pregnancy to study effects of intrauterine exposure to maternal hyperglycemia on neocortical neurogenesis. We observed morphological changes in the neocortex and detected the neurogenetic differentiation of neural stem cells in offspring affected by high glucose levels. We investigated the regulatory network between epigenetic modification and transcription factors in differentiated neural stem cells under hyperglycemic conditions. Maternal hyperglycemia disturbs neocortical lamination in some non-malformed offspring. Our results suggested that hyperglycemia altered the early-born neuron fate and the distribution of newborn neurons in deep layers by promoting the earlier differentiation of neural stem cells. Altered histone acetylation and its regulation on the transcription of proneural genes might be correlated to the disrupted differentiation of neural stem cells and altered distribution of newborn projection neurons in the neocortex. Our data raised the possibility that maternal hyperglycemia in pregnancy disturbs the laminar distribution of neocortical projection neurons in some non-malformed offspring via epigenetic regulation on neural stem cell differentiation and the birthdate of neocortical neurons.
母亲在怀孕期间血糖过高，其子女长期患有神经精神疾病的发病率高于正常妊娠的子女，这表明新皮层神经发生可能受到母体高血糖的影响。评估高血糖对神经干细胞新皮层神经发生分化影响的研究很少，其机制尚不清楚。我们试图研究母体高血糖对神经干细胞新皮层神经发生分化的作用及其可能的分子机制。我们建立了一个高血糖妊娠的小鼠模型，以研究宫内暴露于母体高血糖对新皮层神经发生的影响。我们观察了受高葡萄糖水平影响的后代新皮层的形态变化，并检测了神经干细胞的神经发生分化。我们研究了在高血糖条件下，分化的神经干细胞中表观遗传修饰和转录因子之间的调控网络。母体高血糖会干扰某些正常发育后代的新皮层分层。我们的结果表明，高血糖通过促进神经干细胞的早期分化，改变了早期出生神经元的命运和新生神经元在深层的分布。组蛋白乙酰化的改变及其对神经前体细胞基因转录的调控可能与神经干细胞分化的紊乱和新皮层新生投射神经元分布的改变有关。我们的数据提出了这样一种可能性，即在怀孕期间，母体高血糖可能通过对神经干细胞分化和新皮层神经元出生日期的表观遗传调控，在某些非畸形后代中扰乱新皮层投射神经元的分层分布。
