P53 independent pathogenic mechanisms contribute to BubR1 microcephaly.
P53 independent pathogenic mechanisms contribute to BubR1 microcephaly.
复制标题
DOI：
10.3389/fcell.2023.1282182
复制
发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
苯并咪唑1B(BUB1B)不受抑制的镶嵌杂色非整倍体(MVA)相关基因萌发编码BUBR1，它是纺锤体组装检查点复合体的核心成员，确保着丝粒-纺锤体的附着，以实现忠实的染色体分离。人类的BUB1B突变和小鼠的BUB1B缺失会导致小头畸形。在小鼠体内没有BubR1的情况下，大量细胞死亡会减少神经发生过程中的皮质细胞。然而，触发细胞死亡的分子和细胞机制尚不清楚。在这项研究中，我们在一个小鼠模型中对有丝分裂BubR1缺陷的神经前体细胞进行了三维成像分析，以显示严重的染色体分离缺陷和结构异常。在BubR1突变体中，染色体缺陷和伴随的DNA损伤导致P53激活和细胞凋亡。为了测试P53细胞死亡通路是否与皮质细胞丢失有关，我们在BubR1缺陷的皮质中共删除了TrP53。值得注意的是，我们发现，在缺失P53的双突变体中，残留的凋亡细胞死亡仍然存在，这表明P53非依赖于细胞的凋亡。此外，双突变小鼠皮质大小和皮质神经元数量的最小挽救表明，在没有p53的情况下，替代死亡机制的引人注目的程度。这项研究证明了MVA患者小头畸形的潜在致病机制，并发现即使在p53死亡途径被禁用的情况下，也存在消除不适合细胞的有效方法。
The mosaic variegated aneuploidy (MVA)-associated gene Budding Uninhibited by Benzimidazole 1B (BUB1B) encodes BUBR1, a core member of the spindle assembly checkpoint complex that ensures kinetochore-spindle attachment for faithful chromosome segregation. BUB1B mutation in humans and its deletion in mice cause microcephaly. In the absence of BubR1 in mice, massive cell death reduces cortical cells during neurogenesis. However, the molecular and cellular mechanisms triggering cell death are unknown. In this study, we performed three-dimensional imaging analysis of mitotic BubR1-deficient neural progenitors in a murine model to show profound chromosomal segregation defects and structural abnormalities. Chromosomal defects and accompanying DNA damage result in P53 activation and apoptotic cell death in BubR1 mutants. To test whether the P53 cell death pathway is responsible for cortical cell loss, we co-deleted Trp53 in BubR1-deficient cortices. Remarkably, we discovered that residual apoptotic cell death remains in double mutants lacking P53, suggesting P53-independent apoptosis. Furthermore, the minimal rescue of cortical size and cortical neuron numbers in double mutant mice suggests the compelling extent of alternative death mechanisms in the absence of P53. This study demonstrates a potential pathogenic mechanism for microcephaly in MVA patients and uncovers the existence of powerful means of eliminating unfit cells even when the P53 death pathway is disabled.
影响因子：
11.8
作者：
Malureanu, Liviu A.;Jeganathan, Karthik B.;Hamada, Masakazu;Wasilewski, Lisa;Davenport, James;van Deursen, Jan M.
通讯作者：
van Deursen, Jan M.