ETMR-26. MIR-34/449 FAMILY PLAYS A CRUCIAL ROLE IN CHOROID PLEXUS MULTICILIATION AND TUMORIGENESIS

Abstract

Abstract BACKGROUND Choroid plexus (CP), an epithelial structure within the brain ventricles, produces cerebrospinal fluid and serves barrier functions in the brain. Primary CP neoplasms are rare intracranial tumors that predominantly occurs in childhood. Recent studies revealed multiciliated cells in the CP in humans and mice. In contrast, benign CP papilloma, and malignant CP carcinoma (CPC) in humans are characterized by solitary cilia, and disturbances to multiciliation program directed by transcription factor GMNC. Additionally, most CPC in humans carry mutations in TP53 tumor suppressor. Consistently, Trp53-deficient CPC in mice display singular cilia consequent to defects in GMNC multiciliation program. Thus, the impairment of multiciliation enables tumor cell proliferation. MicroRNAs (miRNAs) are non-coding small RNAs with gene regulatory functions. Specifically, the mir-34/449 family comprises of six miRNAs collaborate to influence multiciliation in diverse tissues but role of mir-34/449 family in the brain is poorly understood. Knowledge of multiciliation program regulation may provide crucial insights into tumor suppression mechanisms in CPC. METHODS To investigate the role of mir-34/449 family in the CP, human CP organoid and mir-34/449 mutant animals were used. RNAscope, In situ hybridization as well as immunofluorescence staining was utilized to identify gene expression in tissues. RESULTS Preliminary studies revealed GMNC program activity and multiciliated cells in CP organoid derived from human induced pluripotent stem cells. Disruption of the mir-34/449 family led to supernumerary cilia and ectopic multiciliation program activity in the CP. Importantly, Trp53-deficient CPC exhibited distinct expression of the mir-34/449 family. Further, sequencing studies revealed an overlap of differentially expressed miRNAs in CP tumors in humans and mice, with an enrichment of the mir-34/449 family. CONCLUSIONS Together, these findings indicate that the mir-34/449 family regulates multiciliation in the CP, whereas the study of its interactions with the multiciliation program holds the key to understanding multiciliation as a tumor suppression pathway in CPC.