Neural　stem　cells　(NSCs)　are　critical　for　brain　development　and　maintenance　of　neurogenesis.　However,　the　molecular　mechanisms　that　regulate　NSC　proliferation　and　differentiation　remain　unclear.　Mysm1　is　a　deubiquitinase　and　is　essential　for　the　self-renewal　and　differentiation　of　several　stem　cells.　It　is　unknown　whether　Mysm1　plays　an　important　role　in　NSCs.　Here,　we　found　that　Mysm1　was　expressed　in　NSCs　and　its　expression　was　increased　with　age　in　mice.　Mice　with　Mysm1　knockdown　by　crossing　Mysm1　floxed　mice　with　Nestin-Cre　mice　exhibited　abnormal　brain　development　with　microcephaly.　Mysm1　deletion　promoted　NSC　proliferation　and　apoptosis,　resulting　in　depletion　of　the　stem　cell　pool.　In　addition,　Mysm1-deficient　NSCs　skewed　toward　neurogenesis　instead　of　astrogliogenesis.　Mechanistic　investigations　with　RNA　sequencing　and　genome-wide　CUT&Tag　analysis　revealed　that　Mysm1　epigenetically　regulated　Id4　transcription　by　regulating　histone　modification　at　the　promoter　region.　After　rescuing　the　expression　of　Id4,　the　hyperproliferation　and　imbalance　differentiation　of　Mysm1-deficient　NSCs　was　reversed.　Additionally,　knockdown　Mysm1　in　aged　mice　could　promote　NSC　proliferation.　Collectively,　the　present　study　identified　a　new　factor　Mysm1　which　is　essential　for　NSC　homeostasis　and　Mysm1-Id4　axis　may　be　an　ideal　target　for　proper　NSC　proliferation　and　differentiation.　©　The　Author(s)　2024.