Gestational Iron Deficiency disrupts neural patterning in the embryo

正常的铁稳态对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，据估计，80%的女性铁储备不足，无法充分供应生长中的胎儿。许多报告发现，即使是边际妊娠期缺铁（GID）也与后代的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受低铁水平影响的特定分子机制和细胞靶点的了解，因果关系仍然难以捉摸。我们现在提供的证据表明，在中间神经元祖细胞出生和增殖的时候，早期GID会导致胚胎大脑中的Shh信号异常。胚胎中Shh信号的异常发生在脂质稳态变化之前，这对于建立合适的Shh信号梯度很重要。由此产生的细胞损伤对出生后的脑功能有长期持续的影响，并且对出生后的铁补充是难解的。基于这些数据，我们提出了一个新的假设，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有关。在Aim 1中，我们将验证暴露于GID的胚胎大脑中Shh信号被破坏导致皮层发育受损的假设。在Aim 2中，我们将验证一个假设，即gid相关的脂质稳态变化是Shh信号域异常变化和下游靶标不适当激活的原因。目的3将检验在小鼠模型中观察到的GID的影响在类似发育阶段的人类组织中也发现的假设。据我们所知，这些数据提供了在胚胎和胎儿大脑发育期间受GID影响的新机制和新细胞靶点。我们描述的缺陷提供了GID与复杂认知障碍的关联的解释，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。

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.