Knockdown of Placental Major Facilitator Superfamily Domain Containing 2a in Pregnant Mice Reduces Fetal Brain Growth and Phospholipid Docosahexaenoic Acid Content.
Knockdown of Placental Major Facilitator Superfamily Domain Containing 2a in Pregnant Mice Reduces Fetal Brain Growth and Phospholipid Docosahexaenoic Acid Content.
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DOI：
10.3390/nu15234956
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发表时间：
2023-11-29
期刊：
影响因子：
5.9
通讯作者：
Jansson T
中科院分区：
文献类型：
--
作者：
Powell TL;Barentsen K;Vaughan O;Uhlson C;Zemski Berry K;Erickson K;Faer K;Chassen SS;Jansson T
简介：二十二碳六烯酸 (DHA) 是一种 n-3 长链多不饱和脂肪酸，对胎儿大脑发育至关重要，通过胎盘从母亲转运至胎儿。溶血磷脂酰胆碱 (LPC) 转运蛋白，主要促进子超家族结构域 2a (MFSD2a)，位于人胎盘合体滋养层的基底质膜中，MFSD2a 表达与人妊娠期脐带血 LPC-DHA 水平相关。我们假设妊娠小鼠胎盘特异性敲除 MFSD2a 会减少胎儿大脑中磷脂 DHA 的积累。方法：用含有靶向 MFSD2a 的 shRNA 或非编码序列 (SCR) 的表达 EGFP 的慢病毒转导小鼠囊胚 (E3.5)，然后转移至假孕雌性体内。在E18.5，对胎儿进行称重并收集其胎盘、大脑、肝脏和血浆。通过 qPCR 测定大脑、肝脏和胎盘中的 MFSD2a mRNA 表达，并通过 LC-MS/MS 定量磷脂 DHA。结果：与 SCR 对照相比，在 E18.5 时，MFSD2a 靶向 shRNA 使胎盘 mRNA MFSD2a 表达降低了 38%（n = 45，p < 0.008）。胎儿大脑和肝脏中的 MFSD2a 表达没有变化。胎儿脑重量减少了 13% (p = 0.006)。体重、胎盘和肝脏重量不受影响。胎盘特异性 MFSD2a 敲低的胎儿中，胎儿脑磷脂酰胆碱和磷脂酰乙醇胺 DHA 含量较低。结论：胎盘特异性 LPC-DHA 转运蛋白 MFSD2a 表达减少导致胎儿脑重量减轻和胎儿脑中磷脂 DHA 含量降低。这些数据提供了机制证据，表明胎盘 MFSD2a 介导 LPC-DHA 的母婴转移，这对大脑生长至关重要。
Introduction: Docosahexaenoic acid (DHA) is an n-3 long chain polyunsaturated fatty acid critical for fetal brain development that is transported to the fetus from the mother by the placenta. The lysophosphatidylcholine (LPC) transporter, Major Facilitator Superfamily Domain Containing 2a (MFSD2a), is localized in the basal plasma membrane of the syncytiotrophoblast of the human placenta, and MFSD2a expression correlates with umbilical cord blood LPC-DHA levels in human pregnancy. We hypothesized that placenta-specific knockdown of MFSD2a in pregnant mice reduces phospholipid DHA accumulation in the fetal brain. Methods: Mouse blastocysts (E3.5) were transduced with an EGFP-expressing lentivirus containing either an shRNA targeting MFSD2a or a non-coding sequence (SCR), then transferred to pseudopregnant females. At E18.5, fetuses were weighed and their placenta, brain, liver and plasma were collected. MFSD2a mRNA expression was determined by qPCR in the brain, liver and placenta and phospholipid DHA was quantified by LC-MS/MS. Results: MFSD2a-targeting shRNA reduced placental mRNA MFSD2a expression by 38% at E18.5 (n = 45, p < 0.008) compared with SCR controls. MFSD2a expression in the fetal brain and liver were unchanged. Fetal brain weight was reduced by 13% (p = 0.006). Body weight, placenta and liver weights were unaffected. Fetal brain phosphatidyl choline and phosphatidyl ethanolamine DHA content was lower in fetuses with placenta-specific MFSD2a knockdown. Conclusions: Placenta-specific reduction in expression of the LPC-DHA transporter MFSD2a resulted in reduced fetal brain weight and lower phospholipid DHA content in the fetal brain. These data provide mechanistic evidence that placental MFSD2a mediates maternal–fetal transfer of LPC-DHA, which is critical for brain growth.
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