Abstract
Choroid plexus (CP) tumors are intraventricular papillary neoplasms mainly found in children. While CP papilloma is a benign tumor, CP carcinoma is malignant and associated with poor prognosis. Though previous studies implicate Notch signaling in CP tumorigenesis, the developmental origin and mechanisms of Notch-induced CP tumors remain unclear. We used the Rosa26-NICD1 strain to express the intracellular domain of Notch 1 (NICD1) using Cre-loxP technologies. Hindbrain CP targeted for NICD1 expression developed abnormal growth consistent with CP papilloma. While Notch-induced CP tumor cells expressed CP markers Lmx1a and Otx2, the expression of Aquaporin 1 (AQP1), marker for differentiated CP epithelium, was absent. Embryonic studies showed that CP tumor arises during development and exhibit properties similar to those of CP epithelial progenitors. However, unlike progenitor cells, tumor cells fail to exit the cell cycle and differentiate into mature CP epithelium. Gene expression studies revealed increased expression of Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in both Notch-induced CP tumors and human CP tumors, suggesting the role of Shh signaling in CP tumors. Conversely, Shh treatment stimulated the proliferation of Notch-induced CP tumor cells. Vertebrate Shh signaling is uniquely dependent on primary cilium. Unlike differentiated CP epithelial cells with small tufts of primary cilia on their apical surface, Notch-induced CP tumor cells only possess solitary primary cilium. Further analysis revealed reduced expression of Foxj1 and Mcidas, crucial regulators of multiciliate differentiation, in tumor cells. Together, these results indicate that Notch-induced CP tumor arises from CP epithelial progenitors during development but lack terminal differentiation; and Notch pathway activation in tumor cells suppresses multiciliate differentiation, thereby allowing Shh-driven proliferation. Our studies demonstrate that Notch and Shh pathways converge on primary cilium to drive CP tumor formation, Shh pathway is a potential therapeutic target for Notch-induced CP tumors.