Gestational Iron Deficiency disrupts neural patterning in the embryo

妊娠期缺铁会破坏胚胎的神经模式

• 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
• 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

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.

正常的铁稳态对于中枢神经系统的健康发育至关重要，而最佳的母体铁储备对于为胎儿发育中的大脑提供足够的铁至关重要。然而，估计 80% 的女性铁储备不足，无法充分供应正在发育的胎儿。许多报告发现，即使是边缘妊娠期缺铁 (GID) 也与后代认知功能受损密切相关。然而，由于缺乏对胚胎中枢神经系统中低铁水平影响的特定分子机制和细胞靶标的了解，因果关系仍然难以捉摸。我们现在提供的证据表明，当中间神经元祖细胞出生和增殖时，早期 GID 会导致胚胎大脑中异常的 Shh 信号传导。胚胎中异常的Shh信号传导先于脂质稳态的变化，这对于建立适当的Shh信号传导梯度非常重要。由此产生的细胞损伤对产后脑功能产生长期持续的影响，并且产后铁补充剂难以治愈。基于这些数据，我们提出了一个新的假设：GID 会导致大脑脂质稳态破坏，从而改变 Shh 信号传导。这种改变的 Shh 信号传导导致神经命运规范和/或增殖的变化，以及出生后大脑皮层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，我们还提出在小鼠模型中进行的观察与人类发育相关。在目标 1 中，我们将检验以下假设：暴露于 GID 的胚胎大脑中的 Shh 信号传导被破坏会导致皮质发育受损。在目标 2 中，我们将检验以下假设：GID 相关的脂质稳态变化是导致 Shh 信号结构域异常变化和下游靶点不适当激活的原因。目标 3 将检验以下假设：在小鼠模型中观察到的 GID 的影响也存在于具有相当发育阶段的人体组织中。据我们所知，这些数据提供了在胚胎和胎儿大脑发育过程中受 GID 影响的新机制和新细胞靶点。我们描述的缺陷解释了 GID 与复杂认知障碍之间的关联，我们使用人类胚胎组织的工作是首次尝试将妊娠 ID 研究从小鼠模型转化为人类。