Gene expression studies have fully described the transcriptional cascades involving the Olig family of bHLH proteins that are required for neuronal stem cells to choose first the glial, and then decide between the oligodendrocyte or astrocyte cell fate; and yet, a gap persists in our understanding of how terminal glial cell identity is maintained and how glia cell function is regulated. This gap in our knowledge presents a critical barrier to our ability to manipulate glial cells to facilitate growth and recovery from injuries to the central nervous system. It also hinders our ability to design effective treatments for glia-associated diseases, including mood altering disorders and neurodegenerative diseases. In Caenorhabditis elegans, the Olig ortholog HLH-17 is strongly and predominantly expressed in the astrocyte-like cells of the cephalic sheath (CEPglia), but is not required for CEPglia specification or differentiation. We hypothesize that HLH-17 is required for the maintenance of CEPglia cell identity, and consequently, for CEPglia to direct normal animal behavior. We can uniquely test this hypothesis in C. elegans because loss of glia cells is not lethal and because neural development, neural connectivity, and neurotransmitter-mediated behaviors all have been thoroughly characterized. These studies will allow us to address overarching goal, which is to determine what distinguishes one glia subtype from another, and to determine how that identity is maintained throughout the life of the organism. The objectives in this pilot application are to (Aim 1) identify glia enriched and subtype-specific transcripts of the C. elegans glia and correlate the glia subtype-specific expression of HLH-17 with the unique molecular signature of that glia;
and (Aim 2) demonstrate that manipulation of glia integrity can be directly correlated with animal behavior. The impact of study will be an improved understanding of the mechanisms (1) by which glia can affect mood disorders associated with dopamine signaling and (2) by which manipulation of Olig and other terminal transcription factors can lead to improved recovery from injury to the CNS. This understanding may ultimately lead to novel therapeutic approaches.
The goal of the proposed research is to determine what distinguishes one glia subtype from another, and to determine how that identity is maintained throughout the life of the organism. The impact of study will be an improved understanding of the mechanisms (1) by which glia can affect mood disorders associated with dopamine signaling and (2) by which manipulation of Olig and other terminal transcription factors can lead to improved recovery from injury to the CNS. This understanding may ultimately lead to novel therapeutic approaches for the treatment of neurodegenerative disorders and mood disorders like depression, ADHD, and schizophrenia. .
