Browsing by Subject "Cell Transdifferentiation"
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Item The Role of NeuroD1 in Physiological and Pathological Neurogenesis(2016-12-05) Brulet, Rebecca R.; Schneider, Jay W.; Hsieh, Jenny; Eisch, Amelia J.; Ge, Woo-PingNeurogenesis in the adult brain is a complex and highly regulated process. Under normal physiological conditions neurogenesis in the hippocampal subgranular zone (SGZ) is important for learning, memory, and mood regulation. What is not well understood, however, is whether in certain disease contexts, like epilepsy, aberrant neurogenesis can contribute to the progression of spontaneous reoccurring seizures (SRS) and associated memory decline. In this work, I present evidence that aberrant hippocampal neurogenesis is causative in the perpetuation of SRS. In an effort to target a select stage of adult neurogenesis I identified the bHLH transcription factor NeuroD1, known to be important in adult neurogenesis, as being strongly upregulated after status epilepticus (SE). Additionally, I show expression of NeuroD1 in aberrant ectopically localized granule cells suggesting a potential role for this transcription factor in the progression of epilepsy. NeuroD1 conditional knockout (cKO) in progenitor cells of the hippocampus may be sufficient to reduce the number of immature and mature neurons amongst the labeled population, however the total number of immature and mature neurons was not significantly changed aside from the immature neurons ectopically localized to the hilus. Consistent with this, the total SRS was unchanged in the NeuroD1 cKO. Transdifferentiation, or the direct inter-lineage conversion of adult somatic cells is a powerful tool with the potential to be used in neuronal replacement strategies in certain neurological disorders or CNS injuries. Transdifferentiation of reactive astrocytes into glutamatergic neurons via retroviral targeting in the cortex can be accomplished by overexpression of the transcription factor NeuroD1. However, what is not well understood is whether the state of reactive gliosis is necessary to "prime" these cells for the transdifferentiation process. In this work I present evidence to suggest that overexpression of NeuroD1 in the absence of reactive gliosis is capable of astrocyte to neuron transdifferentiation, however the total number of converted cells is vastly lower than what was previously published, suggesting that reactive gliosis does indeed enhance and facilitate the conversion process.Item Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming(2016-07-12) Smith, Derek Kurtis; Johnson, Jane E.; Kim, Tae-Kyung; Olson, Eric N.; Zhang, Chun-LiThe activity of pro-neural signaling molecules and transcription factors is sufficient to induce the transdifferentiation of lineage-restricted fibroblasts into functional neurons; however, a mechanistic model of the immediate-early events that catalyze this conversion has not been well defined. We utilized a high-efficiency reprogramming system of NEUROG2, forskolin (F), and dorsomorphin (D) to characterize the genetic and epigenetic events that initiate an acquisition of neuronal identity in fetal human fibroblasts. NEUROG2 immediately activates a neurogenic program, but is only sufficient to impart a functional identity in the presence of FD. These small molecules promote NEUROG2 and CREB1 co-transcription, induce SOX4 expression, and promote SOX4-dependent chromatin remodeling. Genome-wide occupancy analysis revealed that SOX4 targets numerous SWI/SNF complex subunits and co-binds with NEUROG2 to enhance the expression of diverse neurogenic factors. The overexpression of SWI/SNF chromatin remodeling factors or treatment with small molecules that modify chromatin accessibility enhanced NEUROG2-mediated neuronal reprogramming of adult human skin fibroblasts. This work represents the first comprehensive mechanism for the immediate events that catalyze neuronal transdifferentiation.