Gestational Iron Deficiency disrupts neural patterning in the embryo

妊娠期缺铁会破坏胚胎的神经模式

基本信息

批准号：
10206213
负责人：
MARGOT MAYER-PROSCHEL
金额：
$ 37.73万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206213
关键词：
Address Adult Affect Animal Model Biochemical Birth Brain Cell Proliferation Cell Survival Cell physiology Cells Cerebral cortex Child Cholesterol Complex Data Defect Development Embryo Embryonic Development Equilibrium Exposure to Ferritin Fetus Genetic Homeostasis Human Human Development Impaired cognition Impairment Interneurons Iron Knowledge Learning Disabilities Link Lipids Malnutrition Mental Retardation Modification Molecular Mothers Mus Neurodevelopmental Impairment Neurologic Neurologic Deficit Neurons Nutritional Outcome Study Pattern Phase Play Population Pregnancy Process Proliferating Proteins Refractory Reporter Reporting Role SHH gene Sampling Signal Transduction Slice Specific qualifier value System Testing Therapeutic Time Tissues Translating Woman Work autism spectrum disorder base brain tissue cell motility cell type cellular targeting cognitive function embryo tissue enzyme pathway excitatory neuron experimental study fetal gliogenesis human tissue in vivo inhibitory neuron iron deficiency iron supplementation migration morphogens mouse model nerve stem cell neural patterning novel offspring postnatal preservation progenitor relating to nervous system smoothened signaling pathway stem cells

项目摘要

Normal iron homeostasis is vital for healthy development of the CNS and optimal maternal iron stores are essential for providing adequate iron to the developing brain of the fetus. However, an estimated 80% of women have insufficient iron reserves to adequately supply the growing fetus. Numerous reports have found a strong association of even marginal gestational iron deficiency (GID) with impaired cognitive function in the offspring. However, a causal link has remained elusive due to a lack of knowledge regarding the specific molecular mechanisms and cellular targets that are affected by low iron levels in the embryonic CNS. We now provide evidence showing that early GID leads to aberrant Shh signaling in the embryonic brain at a time when interneuron progenitors are born and proliferate. The aberrant Shh signaling in the embryo is preceded by changes in lipid homeostasis, which is important for establishing a proper Shh signaling gradient. The resulting cellular impairments have long lasting persistent consequences for postnatal brain function and are refractory to post-natal iron supplementation. Based on these data we propose the novel hypothesis that GID leads to disruption in brain lipid homeostasis, which consequently alters Shh signaling. This altered Shh signaling leads to changes in neural fate specification and/or proliferation and a disruption of the balance between excitatory and inhibitory neurons in the postnatal cerebral cortex. Considering the highly preserved cellular processes that are affected by GID, we also propose that the observations made in the murine model are relevant for human development. In Aim 1, we will test the hypothesis that disrupted Shh signaling in embryonic brains exposed to GID causes impaired cortical development. In Aim 2 we will test the hypothesis that GID-associated changes in lipid homeostasis are the reasons for the aberrant changes in the Shh signaling domain and inappropriate activation of downstream targets. Aim 3 will test the hypothesis that the impact of GID observed in mouse models is also found in human tissues of comparable developmental stages. To our knowledge these data provide a novel mechanism and novel cellular targets that are affected by GID during embryonic and fetal brain development. The defects we describe provide an explanation of the association of GID with complex cognitive impairments, and our work using human embryonic tissue is the first attempt to translate studies on gestational ID from murine models to humans.

正常的铁稳态对于CNS的健康发展至关重要，最佳母体铁储存对于为胎儿发育中的大脑提供足够的铁至关重要。但是，估计有80％的女性没有足够的铁储备来充分供应胎儿的增长。许多报道发现，即使边缘妊娠铁缺乏症（GID）与后代的认知功能受损有很强的联系。然而，由于缺乏有关特定分子机制和细胞靶标的知识，该因果关系仍然难以捉摸，这些特定分子机制和细胞靶标受胚胎中枢神经系统中低铁的影响。现在，我们提供的证据表明，早期的GID会导致胚胎大脑中异常的SHH信号传导，而在中间神经元祖细胞出生并扩散的时候。胚胎中的异常SHH信号传导之前是脂质稳态的变化，这对于建立适当的SHH信号梯度很重要。由此产生的细胞损伤对产后脑功能产生了持久的持久后果，并且对产后铁的补充是难治性的。基于这些数据，我们提出了一个新的假设，即GID会导致脑脂质稳态的破坏，从而改变SHH信号。这种改变的SHH信号导致神经命运规格和/或增殖的变化，以及在产后大脑皮层中兴奋性和抑制性神经元之间平衡的破坏。考虑到受GID影响的高度保存的细胞过程，我们还提出，鼠模型中的观察结果与人类的发展有关。在AIM 1中，我们将测试以下假设：暴露于GID的胚胎大脑中的SHH信号传导导致皮质发育受损。在AIM 2中，我们将测试以下假设：脂质稳态的GID相关变化是SHH信号域发生异常变化和下游靶标的不适当激活的原因。 AIM 3将检验以下假设：在相当的发育阶段的人体组织中也发现了在小鼠模型中观察到的GID的影响。据我们所知，这些数据提供了一种新颖的机制和新颖的细胞靶标，这些靶标在胚胎和胎儿脑发育过程中受GID的影响。我们描述的缺陷提供了对GID与复杂认知障碍的关联的解释，而我们使用人类胚胎组织的工作是将妊娠ID研究从鼠模型转化为人类的首次尝试。