Elucidating the Role of Sonic Hedgehog Signaling in Cells Along the Astrocyte Lineage

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PROJECT SUMMARY The goal of this proposal is to determine whether molecularly distinct progenitor cells give rise to local astrocyte diversity. Astrocytes are estimated to comprise up to 40% of cells in the brain and growing evidence now shows that these cells possess diverse phenotypic and molecular characteristics. Nevertheless, large gaps remain in our understanding of how such distinct characteristics arise. This study focuses on the role of the molecular signaling pathway, Sonic hedgehog (Shh), which distinguishes a population of perinatal glial progenitor cells in the forebrain. Fate mapping experiments show that these progenitors generate half the population of cortical astrocytes, suggesting that the cortex harbors astrocytes from multiple lineages. The precise role of Shh signaling in astrocyte development is not well understood. This study applies molecular genetic tools together with high resolution imaging and 3D reconstruction of single cells, together with RNASeq and bioinformatic analysis to address the role of Shh signaling in defining lineage-specific phenotypic and molecular characteristics of astrocytes. We will first identify the progenitor cell responsible for Shh-mediated astrocyte production and define unique characteristics of cells within this lineage. We will then apply loss of function strategies together with RNASeq and bioinformatic analysis to interrogate the role of Shh signaling in astrocyte development and molecular identity. Finally, we will use a cellular ablation approach to determine the functional significance of cells derived from the Shh lineage. This study will advance our understanding of astrocyte diversity in the brain and illuminate novel roles for Shh signaling in cell and brain development.