Department of Biological Sciences, University of Alaska Anchorage, 3101 Science Circle, Anchorage, AK 99508, USA.
Mech Dev. 2012 Sep-Dec;129(9-12):324-38. doi: 10.1016/j.mod.2012.06.001. Epub 2012 Jun 9.
Williams Syndrome Transcription Factor (WSTF) is one of ∼25 haplodeficient genes in patients with the complex developmental disorder Williams Syndrome (WS). WS results in visual/spatial processing defects, cognitive impairment, unique behavioral phenotypes, characteristic "elfin" facial features, low muscle tone and heart defects. WSTF exists in several chromatin remodeling complexes and has roles in transcription, replication, and repair. Chromatin remodeling is essential during embryogenesis, but WSTF's role in vertebrate development is poorly characterized. To investigate the developmental role of WSTF, we knocked down WSTF in Xenopus laevis embryos using a morpholino that targets WSTF mRNA. BMP4 shows markedly increased and spatially aberrant expression in WSTF-deficient embryos, while SHH, MRF4, PAX2, EPHA4 and SOX2 expression are severely reduced, coupled with defects in a number of developing embryonic structures and organs. WSTF-deficient embryos display defects in anterior neural development. Induction of the neural crest, measured by expression of the neural crest-specific genes SNAIL and SLUG, is unaffected by WSTF depletion. However, at subsequent stages WSTF knockdown results in a severe defect in neural crest migration and/or maintenance. Consistent with a maintenance defect, WSTF knockdowns display a specific pattern of increased apoptosis at the tailbud stage in regions corresponding to the path of cranial neural crest migration. Our work is the first to describe a role for WSTF in proper neural crest function, and suggests that neural crest defects resulting from WSTF haploinsufficiency may be a major contributor to the pathoembryology of WS.
威廉姆斯综合征转录因子（WSTF）是患有复杂发育障碍威廉姆斯综合征（WS）的患者中约 25 个单倍体缺失基因之一。WS 导致视觉/空间处理缺陷、认知障碍、独特的行为表型、特征性的“小精灵”面部特征、低肌张力和心脏缺陷。WSTF 存在于几种染色质重塑复合物中，在转录、复制和修复中发挥作用。染色质重塑在胚胎发生过程中至关重要，但 WSTF 在脊椎动物发育中的作用尚未得到充分描述。为了研究 WSTF 的发育作用，我们使用靶向 WSTF mRNA 的莫洛利诺针对 Xenopus laevis 胚胎中的 WSTF 进行敲低。在 WSTF 缺陷型胚胎中，BMP4 的表达明显增加且空间异常，而 SHH、MRF4、PAX2、EPH4 和 SOX2 的表达严重降低，伴随着许多发育中的胚胎结构和器官的缺陷。WSTF 缺陷型胚胎表现出前神经发育缺陷。神经嵴的诱导，通过神经嵴特异性基因 SNAIL 和 SLUG 的表达来衡量，不受 WSTF 耗竭的影响。然而，在随后的阶段，WSTF 敲低导致神经嵴迁移和/或维持的严重缺陷。与维持缺陷一致，WSTF 敲低在尾部阶段在与颅神经嵴迁移路径相对应的区域显示出特定的凋亡增加模式。我们的工作首次描述了 WSTF 在适当的神经嵴功能中的作用，并表明 WSTF 单倍体不足导致的神经嵴缺陷可能是 WS 病理胚胎学的主要贡献者。
