GDF11 Expression and Roles during Adult Hippocampal Neurogenesis

Abstract

Growth differentiation factor 11 (GDF11) is a TGFβ superfamily member that acts as a critical negative regulator of developmental neurogenesis. However, very little is known about the CNS expression and functions of endogenous GDF11 during adulthood. Studies investigating the therapeutic potential of GDF11 demonstrated that systemic administration of recombinant GDF11 (rGDF11) promotes, rather than inhibits, neurogenesis in aged mice. This raised questions about how to reconcile the pro-neurogenesis activities of rGDF11 with the anti-neurogenesis functions of GDF11 during development. The goal of this dissertation was to resolve this discrepancy and address the gap in knowledge surrounding endogenous GDF11’s functions during adulthood. To better understand the cellular sources of Gdf11 in the adult mouse brain, I performed a quantitative histological analysis of Gdf11 expression. I determined that Gdf11 is highly expressed in the hippocampus, choroid plexus, thalamus, and neurogenic zones by cells of the neuronal, glial and ependymal cell lineages. The contribution of endogenous GDF11 to adult neurogenesis was then investigated using a tamoxifen inducible mouse to reduce GDF11 levels. Reducing Gdf11 increased proliferation of adult neural progenitors and decreased the number of newborn hippocampal neurons. These findings reveal that GDF11 expressed in the adult brain acts as a negative regulator of neurogenesis, as it does during development. It suggests that rGDF11 administered to the blood and brain derived GDF11 have different mechanisms of action. The expression of Gdf11 in nonneurogenic adult brain regions suggested GDF11 may contribute to additional biological processes. To identify novel hippocampal functions for GDF11, bulk RNA-sequencing was performed on adult hippocampi isolated after Gdf11 depletion. Genes involved in myelination and glial cell development were significantly downregulated while genes associated with neuronal activity were upregulated. Using immunohistochemistry, I observed fewer oligodendrocyte progenitor cells and myelination deficits across the entire hippocampus after Gdf11 depletion. These data lay the groundwork for future investigations into how GDF11 contributes to diverse activities throughout the adult brain. Overall, these studies uncover significant new roles for GDF11 during adulthood and provide biological insight relevant for its therapeutic potential.