Understanding the developmental progression of subpallial neural progenitor cells

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.

Grant Number: 5R01NS119760-04
NIH Institute/Center: NIH
Principal Investigator: Xinwei Cao