Astrocytes, the most populous glial cell in the central nervous system (CNS), play essential role in brain
development and function including ion/neurotransmitter homeostasis, synapse formation/removal and
synaptic transmission modulation. These crucial functions are molecularly determined by their gene signatures
which are controlled by nuclear transcription factors. In response to neurological diseases and injuries,
astrocytes become reactive astrocytes and adopt neurotoxic and/or neuroprotective functions which modulate
CNS pathophysiology. The ultimately functional output of reactive astrocytes is determined by their differential
gene expression signature which is controlled transcriptional factors. Our long-term goal has been centered on
unveiling mechanisms underlying CNS glial cell homeostasis and pathophysiology with a focus on the
transcription factor SOX2. We found that SOX2 is highly enriched in adult quiescent astrocytes and retained in
reactive astrocytes in response to inflammatory demyelinating injury. However, little is known about the
functional significance of SOX2 in regulating astrocyte biology and pathology. Recently, we reported a crucial
role of SOX2 in astrocyte maturation and animal behavior. As a transcription factor, SOX2 binds to the
regulatory elements of a cohort of astrocytic signature and functional genes and modulates their expression.
These data highlight the importance of SOX2 in astrocyte development and function. We employed a “top-
down” approach to investigate functional significance of SOX2 in adult astrocytes. Astrocyte-specific SOX2
conditional knockout (cKO) results in hyperactive locomotor yet normal motor coordination and cognition
functions. Furthermore, astrocyte SOX2 cKO mice develop worse clinical symptoms in response to EAE injury.
In this project, we will test the hypothesis that SOX2 is essential for adult astrocyte homeostasis and function
and its deficiency in reactive astrocytes exacerbates inflammatory demyelinating injury. This project, upon
completion, will provide the first conceptual landscape of the functional significance of SOX2 in quiescent
astrocytes and reactive astrocytes.