Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Development. 2023 Oct 1;150(19). doi: 10.1242/dev.202139. Epub 2023 Oct 10.
Closed spinal dysraphisms are poorly understood malformations classified as neural tube (NT) defects. Several, including terminal myelocystocele, affect the distal spine. We have previously identified a NT closure-initiating point, Closure 5, in the distal spine of mice. Here, we document equivalent morphology of the caudal-most closing posterior neuropore (PNP) in mice and humans. Closure 5 forms in a region of active FGF signalling, and pharmacological FGF receptor blockade impairs its formation in cultured mouse embryos. Conditional genetic deletion of Fgfr1 in caudal embryonic tissues with Cdx2Cre diminishes neuroepithelial proliferation, impairs Closure 5 formation and delays PNP closure. After closure, the distal NT of Fgfr1-disrupted embryos dilates to form a fluid-filled sac overlying ventrally flattened spinal cord. This phenotype resembles terminal myelocystocele. Histological analysis reveals regional and progressive loss of SHH- and FOXA2-positive ventral NT domains, resulting in OLIG2 labelling of the ventral-most NT. The OLIG2 domain is also subsequently lost, eventually producing a NT that is entirely positive for the dorsal marker PAX3. Thus, a terminal myelocystocele-like phenotype can arise after completion of NT closure with localised spinal mis-patterning caused by disruption of FGFR1 signalling.
闭合性脊柱脊膜膨出是一种理解不充分的畸形，被归类为神经管（NT）缺陷。其中一些，包括终末脊髓脊膜膨出，影响脊柱的远端。我们之前在小鼠的远端脊柱中发现了一个 NT 闭合起始点，即 Closure 5。在这里，我们记录了小鼠和人类最尾端闭合的后神经孔（PNP）的等效形态。Closure 5 形成于 FGF 信号活跃的区域，而药理学 FGF 受体阻断会损害其在培养的小鼠胚胎中的形成。Cdx2Cre 条件性遗传删除尾部胚胎中的 Fgfr1 会减少神经上皮细胞的增殖，损害 Closure 5 的形成并延迟 PNP 的闭合。闭合后，Fgfr1 破坏的胚胎的远端 NT 会扩张，形成一个充满液体的囊，覆盖在腹侧扁平的脊髓上。这种表型类似于终末脊髓脊膜膨出。组织学分析显示，SHH 和 FOXA2 阳性的腹侧 NT 区域出现区域性和进行性丧失，导致 OLIG2 标记腹侧最 NT。OLIG2 区域随后也会丢失，最终产生一个完全对背侧标记物 PAX3 呈阳性的 NT。因此，在 NT 闭合完成后，由于 FGFR1 信号的破坏导致局部脊柱模式错乱，可能会出现类似于终末脊髓脊膜膨出的表型。
