Project Summary The embryonic ventral telencephalon, the subpallium, is the developmental origin of numerous brain structures and cell populations such as the basal ganglia and cortical interneurons. These structures and cell populations are critical for higher brain functions and are often causally involved in neuropsychiatric disorders such as schizophrenia, autism, and drug addiction. Thus, a better understanding of ventral telencephalon development will not only improve our understanding of brain development and brain function but also advance treatments of nervous system disorders. All neurons and glia generated in the ventral telencephalon are descendants of subpallial neural progenitor cells (NPCs), which here broadly include multipotent stem/progenitor cells known as apical progenitors (APs) and lineage-restricted transit-amplifying cells known as basal or intermediate progenitors (BPs). Because research on NPCs during mammalian brain development has focused on the cortex, comparatively little is known about the steps of the developmental progression of subpallial NPCs and the mechanisms involved, although it is evident that subpallial NPCs must possess unique features that underlie their distinct cellular outputs (in terms of cell number and cell type). The objective of this application is to investigate the cellular and molecular mechanisms that control the developmental progression of subpallial NPCs. Recently, by analyzing a conditional knockout mouse line lacking Tead1 and Tead2, which encode key transcription factors of the Hippo pathway—a signaling pathway crucial for the development, tumorigenesis, and regeneration of most tissues across species, we found that the TEAD transcription factors are novel regulators of the developmental progression of subpallial NPCs; they uniquely regulate subpallial, but not pallial (cortical), NPCs and act through Hippo pathway-dependent and -independent mechanisms. The central hypothesis of this proposal is that TEAD regulates the developmental progression of subpallial NPCs with a dual mode of action: in APs, TEAD interacts with YAP/TAZ to maintain the AP state; in BPs, however, TEAD interacts with INSM1 to repress the AP state and promote developmental progression. Specifically, the proposed study will: (1) dissect the role of TEAD in subpallium development by using various genetic modified mouse models, (2) determine whether TEAD acts through INSM1 in subpallial basal progenitors, and (3) define the transcriptional mechanism through which TEAD regulates subpallial NPCs. The proposed study is expected to expand our knowledge of the mechanisms that uniquely regulate the developmental progression of subpallial NPCs and improve our understanding of an important signaling pathway—the Hippo pathway.