Abstract：
Neural tube closure is a dynamic morphogenic event in early embryonic development. Perturbations of this process through either environmental or genetic factors induce the severe congenital malformations known collectively as neural tube defects (NTDs). Deficiencies in maternal folate intake have long been associated with NTDs, as have mutations in critical neurulation genes that include the Grainyhead-like 3 (Grhl3) gene. Mice lacking this gene exhibit fully penetrant thoraco-lumbo-sacral spina bifida and a low incidence of exencephaly. Previous studies have shown that exposure of pregnant mice carrying hypomorphic Grhl3 alleles to exogenous retinoic acid (RA) increases the incidence and severity of NTDs in their offspring. Here, we demonstrate that inhibition of RA signaling using a high affinity pan-RA receptor antagonist administered to pregnant mice at E7.5 induces fully penetrant exencephaly and more severe spina bifida in Grhl3-null mice. Later administration, although prior to neural tube closure has no effect. Similarly, blockade of RA in the context of reduced expression of Grhl2, a related gene known to induce NTDs, has no effect. Taken together, these findings provide new insights into the complexities of the interplay between RA signaling and Grhl3-induced neurulation.
摘要：
神经管闭合是早期胚胎发育中的动态形态发生事件。通过环境或遗传因素对该过程的干扰会导致严重的先天性畸形，统称为神经管缺陷（NTDs）。长期以来，母亲叶酸摄入量不足与NTDs有关，包括Grainyhead样3（Grhl3）基因在内的关键神经代谢基因也有突变。缺乏该基因的小鼠表现出完全渗透的胸腰骶脊柱裂和外脑畸形发生率低。先前的研究表明，携带低形态Grhl3等位基因的怀孕小鼠暴露于外源性视黄酸（RA）会增加其后代NTD的发生率和严重程度。这里,我们证明,在Grhl3-null小鼠中,使用高亲和力pan-RA受体拮抗剂对妊娠小鼠在E7.5时的RA信号传导抑制可诱导完全渗透性脑外裂和更严重的脊柱裂.后来的管理，虽然在神经管闭合之前没有效果。同样，在Grhl2（一种已知诱导NTDs的相关基因）表达降低的情况下阻断RA，没有效果。一起来看,这些发现为RA信号传导和Grhl3诱导的神经形成之间相互作用的复杂性提供了新的见解。
