Genetic interplay between the transcription factors Sp8 and Emx2 in the patterning of the forebrain

Using conditional inactivation, we show that the transcription factor Sp8 has an essential role in the molecular and functional patterning of the developing telencephalon along the anteroposterior axis by modulating the expression gradients of Emx2 and Pax6. Moreover, Sp8 is essential for the maintenance of ventral cell identity in the septum and medial ganglionic eminence (MGE). This is probably mediated through a positive regulatory interaction with Fgf8 in the medial wall, and Nkx2.1 in the rostral MGE anlage, and independent of SHH and WNT signaling. Furthermore, Sp8 is required during corticogenesis to sustain a normal progenitor pool, and to control preplate splitting, as well as the specification of cellular diversity within distinct cortical layers.The mammalian forebrain, with its components the basal ganglia (subpallium) and cortex (pallium), is a result of advanced evolutionary processes. Although several genetic pathways that establish cell diversity within the developing telencephalon have been identified, only a few factors have been shown to control the earliest steps of anteroposterior (A/P) and dorsoventral (D/V) patterning [1].From embryonic stage E7.5 onwards, the telencephalic vesicles are progressively regionalized through complex interactions of secreted ligands from inductive centers, and by the regionalized or graded expression of transcription factors [1-3]. FGF (Fibroblast Growth Factor) signaling acts downstream of SHH (Sonic Hedgehog) and is required to both specify and promote the proliferation and/or survival of ventral cell types in the telencephalon [4-7], while WNT (Wint) signaling apparently elaborates archicortical morphogenesis [8,9]. Interestingly, modulation of the normal expression gradient of Fgf8 in the early cortical primordium alters the molecular location and the size of cortical domains along the A/P axis [10,11]. At the beginning of cortical neurogenesis, several transcription factors display graded expression in cortica