scholarly journals Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus

Development ◽  
2009 ◽  
Vol 136 (15) ◽  
pp. 2535-2543 ◽  
Author(s):  
X. Huang ◽  
T. Ketova ◽  
J. T. Fleming ◽  
H. Wang ◽  
S. K. Dey ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Progenitor Domain

CSIG-28. REGULATION OF GEMC1 MULTICILIOGENESIS PROGRAM IN CHOROID PLEXUS CARCINOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi39-vi39
Author(s):  
Haotian Zhao ◽  
Thomas Page ◽  
Tamanna Sarowar
Keyword(s):  
Epithelial Cells ◽  
Choroid Plexus ◽  
Tumor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Coiled Coil ◽  
Apical Surface ◽  
Cell Cycle Protein ◽  
Sonic Hedgehog Signaling ◽  
Therapeutic Avenue

Abstract Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.

scholarly journals RARE-14. DISRUPTION OF GEMC1-MCIDAS MULTICILIOGENESIS PROGRAM PROMOTES CHOROID PLEXUS CARCINOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i43-i43
Author(s):  
Navleen Singh ◽  
Tamanna Sarowar ◽  
Tasneerm Zahran ◽  
Haotian Zhao
Keyword(s):  
Epithelial Cells ◽  
Choroid Plexus ◽  
Tumor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Coiled Coil ◽  
Apical Surface ◽  
Cell Cycle Protein ◽  
Sonic Hedgehog Signaling ◽  
Therapeutic Avenue

Abstract Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.

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