INTRODUCTION: Neurofibromatosis type 2 (Nf2) gene inactivation is common in sporadic and Nf2-related meningioma. There is currently scant literature describing the development of an intracranial meningioma model in animals. Given the role of Nf2 and other gene inactivation in meningeal cells, we used Cas9 mice here as the background host to establish a new animal model of skull base meningioma in this study. AIMS: Cas9 transgenic mice were purchased from Jackson Laboratory and raised in our institution. Subsequently, meningeal cells were obtained from the Cas9 transgenic mice, cultured in medium, and passaged in vitro. We then prepared lentivirus vector pLentiCre/gRNA, which could express the elements blocking the function of four genes: Nf2, P15 RESULTS: Twenty Cas9 transgenic mice were successfully bred. Five mice were killed so that meningeal cells could be extracted, cultured, and infected with the lentivirus vector pLentiCre/gRNA for 72 h in vitro. The gene function test showed that Nf2, P15 CONCLUSIONS: The Cas9 mouse model of skull base meningioma generated with the Nf2 genetic defect and the combinational loss of P15