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Koszka, Kathryn

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Koszka

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Kathryn

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Koszka, Kathryn
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    Nanog-Independent Reprogramming to iPSCs with Canonical Factors
    (Elsevier, 2014) Carter, Ava C.; Davis-Dusenbery, Brandi N.; Koszka, Kathryn; Ichida, Justin K.; Eggan, Kevin
    Summary It has been suggested that the transcription factor Nanog is essential for the establishment of pluripotency during the derivation of embryonic stem cells and induced pluripotent stem cells (iPSCs). However, successful reprogramming to pluripotency with a growing list of divergent transcription factors, at ever-increasing efficiencies, suggests that there may be many distinct routes to a pluripotent state. Here, we have investigated whether Nanog is necessary for reprogramming murine fibroblasts under highly efficient conditions using the canonical-reprogramming factors Oct4, Sox2, Klf4, and cMyc. In agreement with prior results, the efficiency of reprogramming Nanog−/− fibroblasts was significantly lower than that of control fibroblasts. However, in contrast to previous findings, we were able to reproducibly generate iPSCs from Nanog−/− fibroblasts that effectively contributed to the germline of chimeric mice. Thus, whereas Nanog may be an important mediator of reprogramming, it is not required for establishing pluripotency in the mouse, even under standard conditions.
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    The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD
    (2014) Suzuki, Naoki; Maroof, Asif; Merkle, Florian; Koszka, Kathryn; Intoh, Atsushi; Armstrong, Ian; Moccia, Rob; Davis-Dusenbery, Brandi N; Eggan, Kevin
    Using transgenic animals harboring a targeted LacZ insertion, we studied the expression pattern of the C9ORF72 mouse ortholog. Unlike most genes mutated in ALS, which are ubiquitously expressed, the C9ORF72-ortholog was most highly transcribed in the neuronal populations sensitive to degeneration in ALS and FTD. Thus, our study provides a potential explanation for the cell type specificity of neuronal degeneration caused by C9ORF72 mutations.
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    A small molecule inhibitor of Tgf-β signaling replaces Sox2 in reprogramming by inducing Nanog
    (Elsevier BV, 2009) Ichida, Justin K.; Blanchard, Joel; Lam, Kelvin; Son, Esther Y.; Chung, Julia E.; Egli, Dieter; Loh, Kyle M.; Carter, Ava C.; Di Giorgio, Francesco P.; Koszka, Kathryn; Huangfu, Danwei; Akutsu, Hidenori; Liu, David; Rubin, Lee; Eggan, Kevin
    The combined activity of three transcription factors can reprogram adult cells into induced pluripotent stem (iPS) cells. However, the transgenic methods used to deliver reprogramming factors have raised concerns regarding the future utility of the resulting stem cells. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to identify small molecules that can replace Sox2 in reprogramming. We show that one of these molecules functions in reprogramming by inhibiting Tgf-β signaling in a stable and trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming through induction of the transcription factor Nanog.