小柯机器人

加拿大病童医院Michael D. Taylor课题组发现，人类菱唇分化的失败是髓母细胞瘤形成的基础。相关论文于2022年9月21日在线发表在《自然》杂志上。

研究人员表示，髓母细胞瘤（MB）包括一组异质性的小儿后脑胚胎性肿瘤，与后脑的早期发育有密切关系。激活Sonic hedgehog信号的突变导致上菱唇（RL）颗粒细胞谱系的Sonic hedgehog MB。相比之下，激活WNT信号的突变导致WNT MB在下层RL。然而，人们对更常发生的第4组（G4）MB知之甚少，认为它产生于单极刷细胞谱系。

研究人员证明，导致G4型MB的体细胞突变会聚在核心结合因子α（CBFA）复合物和影响CBFA2T2、CBFA2T3、PRDM6、UTX和OTX2的互斥性改变。CBFA2T2在人类小脑RL下区的祖细胞中早期表达，G4 MB的转录与这些祖细胞相似，但在发育时间上是停滞的。在模型系统中敲除OTX2可以解除这种分化阻断，这使得MB细胞可以自发地沿着正常的发育分化轨迹进行。分开的人类RL的特殊性质注定要产生人类大脑中的大部分神经元，其高水平的且易受影响的EOMES⁺KI67⁺单极刷细胞祖细胞可能使人类这个物种容易发展成G4 MB。

附：英文原文

Title: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author: Hendrikse, Liam D., Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H., Erickson, Anders W., Ong, Winnie, Gordon, Victor, Coudire-Morrison, Ludivine, Mercier, Audrey L., Shokouhian, Mohammad, Surez, Ral A., Ly, Michelle, Borlase, Stephanie, Scott, David S., Vladoiu, Maria C., Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J. Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y., Kumar, Sachin A., Balin, Polina, Visvanathan, Abhirami, Lee, John J. Y., Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L., Luu, Betty, Brub, Pierre, Wang, Yu C., Pfister, Stefan M., Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, Franois, Masliah-Planchon, Julien, Grajkowska, Wieslawa A., Loukides, James, Dirks, Peter, Fvre-Montange, Michelle, Jouvet, Anne, French, Pim J., Kros, Johan M., Zitterbart, Karel, Bailey, Swneke D., Eberhart, Charles G.

Issue&Volume: 2022-09-21

Abstract: Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1,2,3,4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5,6,7,8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

DOI: 10.1038/s41586-022-05215-w

Source: https://www.nature.com/articles/s41586-022-05215-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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