Rnf112 is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is regulated during brain development. Our previous study has revealed that Rnf112 can promote neuronal differentiation by inhibiting the progression of the cell cycle in cell models. In this study, we further revealed the important functions of Rnf112 in embryo development and in adult brain. Our data showed that most of the Rnf112−/− embryos exhibited blood vascular defects and died in utero. Upon further investigation, we found that the survival rate of homozygous Rnf112 knockout mice in 129/sv and C57BL/6 mixed genetic background was increased. The survived newborns of Rnf112−/− mice manifested growth retardation as indicated by smaller size and a reduced weight. Although the overall organization of the brain did not appear to be severely affected in Rnf112−/− mice, using in vivo 3D MRI imaging, we found that when compared to wild-type littermates, brains of Rnf112−/− mice were smaller. In addition, Rnf112−/− mice displayed impairment of brain functions including motor balance, and spatial learning and memory. Our results provide important aspects for the study of Rnf112 gene functions.