Browsing by Subject "Spinal Cord"
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Item Modulation of Excitatory and Inhibitory Neuronal Balance Through Regulation of Ptf1a by Factors Binding to Zinc Finger and POU Motifs(2014-05-01) Avila, John Manuel, Jr.; MacDonald, Raymond J.; Wu, Jiang I.; Hsieh, Jenny; Johnson, Jane E.The proper function of the nervous system depends on a delicate balance between excitatory and inhibitory neurons. Transcription factors of the basic helix-loop-helix (bHLH) family have been shown to be particularly important in generating the correct numbers of these neurons during development. One of these, Ptf1a, is required in the specification of inhibitory neurons in multiple regions of the nervous system including the dorsal spinal cord. The absence of Ptf1a in null mice disrupts the balance of excitatory and inhibitory neurons, as Ptf1a is required for generating inhibitory neurons while suppressing the excitatory phenotype. Therefore, discovering the regulators of Ptf1a expression will identify mechanisms controlling the generation of a balanced neural network required for processing somatosensory information. Using sequence conservation between divergent vertebrate species, a 1.2 kb enhancer that directs expression of a reporter gene to Ptf1a expressing domains in transgenic mice was identified approximately 11 kb 3’ of the coding region. A series of mutations across the 1.2 kb enhancer were generated to identify sequences required for activity of this enhancer. The activity of the enhancer in directing expression specifically to the developing dorsal neural tube requires at least two distinct motifs: a putative POU motif required for activity, and a zinc finger which represses activity in non-Ptf1a-expressing populations within the neural tube. The activities of these two motifs were tested by in chick and transgenic mice. Coupled with a bioinformatics approach, several candidates for the upstream transcription factors have been identified and were tested for their role in regulating the temporal and spatial specific-activity of the Ptf1a-enhancer. One factor, Zic1 was shown to repress expression of Ptf1a. Thus, a combination of transcriptional activators and repressors are required to control Ptf1a expression, which regulates the subsequent balanced generation of inhibitory and excitatory neurons in the dorsal spinal cord.Item The Role of Ascl1 in NG2 Cells in the Spinal Cord(2015-01-26) Kelenis, Demetra; Johnson, Jane; Vue, Tou YiaNG2 cells, one of the major glial cell populations within the central nervous system (CNS), are highly proliferative cells identified by the expression of the NG2 proteoglycan. Throughout life, NG2 cells can differentiate into oligodendrocytes to myelinate axon fibers, or they can be maintained in a proliferative or quiescent state as NG2 cells indefinitely. A recent study showed that deletion of tumor suppressor genes specifically within NG2 cells was sufficient to produce brain tumors in a mouse model, indicating that NG2 cells may serve as a potential cell of origin for gliomas. At present, however, understanding of how NG2 cells are regulated to proliferate or differentiate in the CNS remains incomplete. Interestingly, Ascl1, a proneural basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in neural progenitor cells, is also expressed in NG2 cells. Although previous studies have shown that the loss of Ascl1 affects the initial specification and differentiation of NG2 cells, the specific role of Ascl1 in NG2 cells during embryonic and postnatal development remains unknown. In this study, we investigated the direct requirement of Ascl1 in NG2 cells during embryonic and postnatal development in the grey matter (GM) and white matter (WM) of the spinal cord. More specifically, we conditionally deleted Ascl1 specifically within NG2 cells (Ascl1-CKO) at E14.5 or at P30 using an NG2-CreERT2 mouse strain in which the tdTomato (tdTom) fluorescence reporter was also incorporated to allow direct visualization of the development of NG2-labeled (tdTom+) cells. We found that Ascl1-CKO at E14.5 resulted in a decrease in the number of tdTom+ cells in the GM, but an increased number of tdTom+ cells in the WM. In contrast, Ascl1-CKO at P30 resulted in a significant reduction in the number of tdTom+ cells in both the GM and WM. Quantification of the percentage of tdTOM-labeled cells that had differentiated to mature oligodendrocytes revealed that Ascl1-CKO at E14.5 does not affect NG2 cell differentiation, while Ascl1-CKO at P30 accelerated NG2 cell differentiation. Taken together, these findings indicate that Ascl1 is differentially required to regulate the number of NG2 cells in the GM and WM during embryonic development, whereas Ascl1 is essential for regulating both the differentiation and number of NG2 cells in the adult CNS.Item [Southwestern News](1995-06-30) Donovan, JenniferItem [Southwestern News](2001-09-13) Genusa, Angela