Abstract：
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.
摘要：
STAMBP的突变已被确定为导致先天性人类小头畸形-毛细血管畸形（MIC-CAP）综合征，一种以全球发育迟缓为特征的罕见遗传疾病，严重的小头畸形,毛细血管畸形,等。先前的生化研究和小鼠功能丧失研究提供了对STAMBP机制的见解，然而,STAMBP缺乏如何导致患者受影响组织畸形仍存在争议.在这项研究中,我们研究了STAMBP在人胚胎干细胞（hESCs）神经分化过程中的功能和潜在机制。我们发现STAMBP对于hESC的多能性维持或神经分化是不必要的。然而,来自STAMBP缺陷型hESC的神经祖细胞（NPC）无法在体外长期维持/扩增。我们发现抗凋亡蛋白CFLAR在那些受影响的NPCs中下调，CFLAR的异位表达挽救了由STAMBP缺乏症引起的NPC缺陷。我们的研究不仅为STAMBP突变患者神经缺陷的机制提供了新的见解，这也表明死亡受体介导的细胞凋亡是体外NPCs长期维持/扩增的障碍，因此抵消这种细胞死亡途径可能有利于体外NPCs的产生。
