Mutations　in　the　human　X-linked　gene　MECP2　are　responsible　for　most　Rett　syndrome　(RTT)　cases,　predominantly　within　its　methyl-CpG-binding　domain　(MBD).　To　examine　the　role　of　MBD　in　the　pathogenesis　of　RTT,　we　generated　two　MeCP2　mutant　constructs,　one　with　a　deletion　of　MAD　(MeCP2-Delta　MBD),　another　mimicking　a　mutation　of　threonine　158　within　the　MBD　(MeCP2-T158M)　found　in　RTT　patients.　MeCP2　knockdown　resulted　in　a　decrease　in　total　dendrite　length,　branching,　synapse　number,　as　well　as　altered　spontaneous　Ca2+　oscillations　in　vitro,　which　could　be　reversed　by　expression　of　full　length　human　MeCP2　(hMeCP2-FL).　However,　the　expression　of　hMeCP2-Delta　MBD　in　MeCP2-silenced　neurons　did　not　rescue　the　changes　in　neuronal　morphology　and　spontaneous　Ca2+　oscillations,　while　expression　of　hMeCP2-T158M　in　these　neurons　could　only　rescue　the　decrease　in　dendrite　length　and　branch　number.　In　vivo　over　expression　of　hMeCP2-FL　but　not　hMeCP2-Delta　MBD　in　adult　newborn　neurons　of　the　dentate　gyrus　also　rescued　the　cell　autonomous　effect　caused　by　MeCP2　deficiency　in　dendrites　length　and　branching.　Our　results　demonstrate　that　an　intact　and　functional　MBD　is　crucial　for　MeCP2　functions　in　cultured　hippocampal　neurons　and　adult　newborn　neurons.