The retrosplenial cortex (Rsp) is a transitional cortex located between the neocortex and archicortex, but the molecular mechanism specifying Rsp from the archicortex remains elusive. We here report that the transcription factor Satb2 is required for specifying Rsp identity during its morphogenesis. In Satb2 CKO mice, the boundary between the Rsp and archicortex [i.e., subiculum (SubC)] disappears as early as E17.5, and Rsp efferent projection is aberrant. Rsp-specific genes are lost, whereas SubC-specific genes are ectopically expressed in Rsp of Satb2 CKO mice. Furthermore, cell-autonomous role of Satb2 in maintaining Rsp neuron identity is revealed by inactivation of Satb2 in Rsp neurons. Finally, Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development.
