Role for TGF-β superfamily signaling in telencephalic GABAergic neuron development

Abstract Signaling mechanisms mediated by the Trans-forming Growth Factor-β (TGF-β) superfamily regulate a variety of developmental processes. Here we show that components of both bone morphogenetic protein/growth differentiation factor and TGF-β/activin/Nodal branches of TGF-β superfamily signaling are expressed in the developing subpallium. Furthermore, Smad proteins, transcriptional effectors of TGF-β signaling, are co-expressed and physically interact in the basal ganglia with Dlx homeodomain tran-scription factors, which are critical regulators of the differen-tiation, migration and survival of telencephalic GABAergic neurons. We also show that Dlx and Smad proteins localize to promoters/enhancers of a number of common telencephalic genes in vivo and that Smad proteins co-activate transcription with Dlx family members, except with certain mutated human DLX proteins identified in autistic individuals. In agreement with these observations, expression of dominant-negative Smads in the developing basal ganglia phenocopies the cell migration defects observed in Dlx1/2-deficient mice. Together, these results suggest that TGF-β superfamily signaling plays a role in telencephalic GABAergic neuron development through functional interactions with Dlx transcription factors