AbstractIn Wnt/β‐catenin signaling pathway, Gsk3β functions to facilitate β‐catenin degradation. Inactivation of Gsk3β in mice causes a cleft palate formation, suggesting an involvement of Wnt/β‐catenin signaling during palatogenesis. In this study, we have investigated the expression pattern, tissue‐specific requirement and function of Gsk3β during mouse palatogenesis. We showed that Gsk3β is primarily expressed in the palatal epithelium, particularly in the medial edge epithelium overlapping with β‐catenin. Tissue‐specific gene inactivation studies demonstrated an essential role for Gsk3β in the epithelium for palate elevation, and disruption of which contributes to cleft palate phenotype in Gsk3β mutant. We observed that expression of Aixn2, a direct target gene of Wnt/β‐catenin signaling, is ectopically activated in the mutant tongue, but not in the palate. Our results indicate that Gsk3β is an intrinsic regulator required in the epithelium for palate elevation, and could act through a pathway independent of Wnt/β‐catenin signaling to regulate palate development. Developmental Dynamics 239:3235–3246, 2010. © 2010 Wiley‐Liss, Inc.