Gestational Iron Deficiency disrupts neural patterning in the embryo

正常的铁稳态对于CNS的健康发育至关重要，并且最佳的母体铁储备对于向发育中的胎儿大脑提供足够的铁是必不可少的。然而，估计有80%的女性铁储备不足，无法为成长中的胎儿提供充足的铁。许多报告发现，即使是轻微的妊娠期缺铁（GID）也与后代认知功能受损有密切关系。然而，由于缺乏有关胚胎CNS中低铁水平影响的特定分子机制和细胞靶点的知识，因果关系仍然难以捉摸。我们现在提供的证据表明，早期GID导致异常的Shh信号在胚胎大脑中的时间，当中间神经元祖细胞出生和增殖。胚胎中异常的Shh信号传导之前是脂质稳态的变化，这对于建立适当的Shh信号传导梯度是重要的。由此产生的细胞损伤对出生后的脑功能具有长期持续的后果，并且对出生后的铁补充是难治的。基于这些数据，我们提出了新的假设，即GID导致脑脂质稳态的破坏，从而改变Shh信号。这种改变的Shh信号传导导致神经命运指定和/或增殖的变化以及出生后大脑皮层中兴奋性和抑制性神经元之间的平衡的破坏。考虑到高度保存的细胞过程，受GID的影响，我们还提出，在小鼠模型中进行的观察与人类发育有关。在目标1中，我们将测试这一假设，即在暴露于GID的胚胎大脑中破坏Shh信号导致皮质发育受损。在目标2中，我们将测试的假设，GID相关的脂质稳态的变化是异常变化的Shh信号结构域和下游靶点的不适当的激活的原因。目的3将检验以下假设：在小鼠模型中观察到的GID影响也存在于发育阶段相当的人体组织中。据我们所知，这些数据提供了一种新的机制和新的细胞靶点，在胚胎和胎儿脑发育过程中受到GID的影响。我们描述的缺陷提供了一个解释的关联GID与复杂的认知障碍，我们的工作使用人类胚胎组织是第一次尝试翻译研究妊娠ID从小鼠模型到人类。

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.