| Autor: |
Jun Wang, Zhongmin Liu, Sudipto Roy, Haotian Zhao, Hart G.W. Lidov, Thomas D Page, Ahmed Abdeltawab, Yuan Huang, Hao Lu, Berta Terré, Travis H. Stracker, Uzayr Arif, Ping Cao, Ryann M. Fame, Ulrich Schüller, Maria K. Lehtinen, Zhiyuan Han, Lizhao Wu, Navleen Singh, Tasneem Zahran, Robert J. Wechsler-Reya, Qun Li, Kameswaran Surendran |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.22.393298 |
| Popis: |
Multiciliated cells (MCCs) in the brain include the ependymal cells and choroid plexus (CP) epithelial cells. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. However, the mechanisms and functional significance of multiciliogenesis in the CP remain unknown. Deregulated oncogenic signals cause CP carcinoma (CPC), a rare but aggressive pediatric brain cancer. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. NOTCH-driven CP tumors were monociliated, whereas disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of GEMC1 and MCIDAS, early regulators of multiciliogenesis. Consistently, GEMC1-MCIDAS function is essential for multiciliation in the CP, and is critical for correcting multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to theGEMC1program are commonly observed in human CPCs characterized by solitary cilia. Consistently, CPC driven by deletion ofTrp53andRb1in mice exhibits a cilia deficit consequent to loss ofGemc1-Mcidasexpression. Taken together, these findings reveal a GEMC1-MCIDAS multiciliation program in the CP critical for inhibiting tumorigenesis, and it may have therapeutic implications for the treatment of CPC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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