Under auspices of this R01 grant we have cloned the bHLH transcription factors Olig1 and Olig2. We have shown that these proteins regulate diverse functions in central nervous system development including specification of motor neurons and oligodendrocytes. The research described here builds upon progress made in the initial funding period. We have three specific aims:
Specific Aim 1 is to define cis- and trans-acting regulatory elements that govern Olig2 expression in the embryonic spinal cord. Our initial focus is on elements driving Olig2 expression during neurogenesis. We have isolated a human Chr. 21-derived BAG clone that encompasses OLIG2 and approximately 116 kb of flanking material. Regulatory elements within this clone are sufficient to rescue motor neuron and oligodendrocyte specification in transgenic mice that are Olig2 null. Preliminary analysis leads to the testable hypothesis that TALE-HoxA class homeodomain proteins bind the enhancer resulting in Olig1 activation specifically in neuroblasts.
Specific Aim 2 is to test the hypothesis that diverse neurogenic and gliogenic functions of Olig2 are regulated by phosphorylation. In preliminary studies we provide compelling evidence that a pair of protein kinase C (PKC) phosphorylation motifs in the carboxyl terminal domain control neurogenic functions of Olig2. We will knock phosphorylation state mutations of these PKC motifs into the wild type Olig2 locus and assess for biological function in developing mice. We will screen for additional phosphorylation sites that are biologically relevant using in ovo electroporation and state-of-art mass spectroscopy techniques.
Specific Aim 3 is to define the role of Olig expression in glioma. In preliminary studies of more than 200 human brain tumors, we have noted that the Olig genes are expressed in 100 percent of human gliomas; moreover, it is the cycling cells within these tumors that are selectively Olig-positive. We will utilize contemporary genetic models of glioma to discriminate between three testable hypothesis: i) all gliomas arise from Olig-positive neural progenitor cells, ii) Olig genes are stringently required for proliferation/survival of glioma stem cells, iii) Olig1 and Olig2 are reporter genes for a signaling pathway common to all gliomas. The proposed work will shed light on fundamental mechanisms that regulate development of the normal brain from multipotent neural progenitor cells. Identification of regulatory factors for glial progenitor cell specification and differentiation will have practical overtones for the therapy of glial-based diseases such as multiple sclerosis and malignant glioma.
|Kelley, Kevin W; Ben Haim, Lucile; Schirmer, Lucas et al. (2018) Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron 98:306-319.e7|
|Schirmer, Lucas; Möbius, Wiebke; Zhao, Chao et al. (2018) Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity. Elife 7:|
|Zhou, Jing; Tien, An-Chi; Alberta, John A et al. (2017) A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 18:3167-3177|
|Sabo, Jennifer K; Heine, Vivi; Silbereis, John C et al. (2017) Olig1 is required for noggin-induced neonatal myelin repair. Ann Neurol 81:560-571|
|Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87|
|Otero, José Javier; Kalaszczynska, Ilona; Michowski, Wojciech et al. (2014) Cerebellar cortical lamination and foliation require cyclin A2. Dev Biol 385:328-39|
|Meijer, Dimphna H; Sun, Yu; Liu, Tao et al. (2014) An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells. J Neurosci 34:8507-18|
|Yuen, Tracy J; Silbereis, John C; Griveau, Amelie et al. (2014) Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell 158:383-396|
|Fancy, Stephen P J; Harrington, Emily P; Baranzini, Sergio E et al. (2014) Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer. Nat Neurosci 17:506-12|
|Potter, Gregory B; Santos, Marta; Davisson, Muriel T et al. (2013) Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease. Hum Mol Genet 22:3397-414|
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