Biology and Biomedical Sciences: Neurosciences
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
SRF is a highly evolutionary conserved activity-dependent transcription factor. Previous studies have shown that neuron-specific deletion of SRF results in deficits in tangential cell migration, guidance-dependent circuit assembly, activity-dependent gene expression, and synaptic plasticity in the hippocampus. However, very little is known in terms of whether SRF participates in earlier aspects of central nervous system development such as neuronal projection establishment, cell-fate specifications, and neural stem cell homeostasis and survival. We report that SRF is critical for development of major axonal tracts in the forebrain. Conditional mutant mice lacking SRF in neural progenitor cells: Srf-Nestin-cKO) exhibit striking deficits in cortical axonal projections including corticostriatal, corticospinal, and corticothalamic tracts, and they show a variable loss of the corpus callosum. Neurogenesis and interneuron specification occur normally in the absence of SRF and the deficits in axonal projections were not due to a decrease or loss in cell numbers. Similar axonal tract deficits were also observed in mutant mice lacking SRF in the developing neurons of neocortex and hippocampus: Srf-NEX-cKO). These findings suggest crucial functional roles for SRF during neuronal development; SRF is specifically required in a cell-intrinsic manner for axonal tract development but is dispensable for cell survival, neurogenesis, neocortical lamination, and neuronal differentiation. Furthermore, we found that deletion of SRF in neural precursor cells in Srf-Nestin-cKO animals results in 40 - 60% loss in astrocytes as well as oligodendrocytes precursor cells at birth. Astrocytes and oligodendrocytes play crucial roles in nearly every facet of brain development and function; abnormalities in glia have important implications in neurological disorders and neurodegenerative diseases. Despite considerable knowledge on the role of several ligand-receptor complexes that regulate astrocyte and oligodendrocyte specification, the transcriptional mechanisms critical for their development in the brain remain unknown. The loss of astrocytes and oligodendrocytes is not due to cell death or increased neurogenesis. SRF-deficient NPCs exhibited normal growth rate and capacity to self-renew but were deficient in glial specification in response to several pro-astrocytic or pro-oligodendrocyte signals in vitro. Similarly, we observed an increase in the number of proliferative cells in the ventricular zone from embryonic day 14 to day 18, suggesting that SRF-deficient precursor cells accumulate as they fail to acquire post-mitotic glial cell-fates. In contrast, conditional SRF deletion in developing forebrain neurons: Srf-NEX-cKO) did not affect astrocyte differentiation, suggesting a cell-autonomous role for SRF in astrocyte specification. Mechanistically, SRF mediates astrocyte fate-choice by regulating Notch2 receptor expression in NPCs, and Notch2 receptor deletion in NPCs phenocopies the deficits in astrocyte specification. Interestingly, conditional SRF deletion in committed astrocytes: Srf-GFAP-cKO) exhibited hypertrophic and gliosis morphology concomitant with a 4-6 fold increase in astrocytes throughout the brain of 4-week old mutant mice. Together, our findings show that SRF is required, but not sufficient, for astrocyte and oligodendrocyte specification in the brain; SRF is necessary in a cell-autonomous manner in NPCs to regulate astrocyte specification and it plays a critical role in committed astrocytes for proper development.
Lu, Puo Yuan, "Serum Response Factor Regulates Multiple Aspects of Central Nervous System Development" (2012). All Theses and Dissertations (ETDs). 714.