Canonical Wnt/β-catenin regulation of liver receptor homolog-1 mediates pluripotency gene expression.
Delineating the signaling pathways that underlie ESC pluripotency is paramount for development of ESC applications in both the research and clinical settings. In culture pluripotency is maintained by leukemia inhibitory factor (LIF) stimulation of two separate signaling axes: Stat3/Klf4/Sox2 and PI3K/Tbx3/Nanog, which converge in the regulation of Oct4 expression. However, LIF signaling is not required in vivo for self-renewal, thus alternate signaling axes likely mediate these pathways. Additional factors that promote pluripotency gene expression have been identified, including the direct regulation of Oct4 by liver receptor homolog-1 (Lrh-1) and β-catenin regulation of Nanog. Here, we present genetic, molecular, and pharmacological studies identifying a signaling axis in which β-catenin promotes pluripotency gene expression in an Lrh-1-dependent manner. Furthermore, Lrh-1 was identified as a novel β-catenin target gene, and Lrh-1 regulation is required for maintaining proper levels of Oct4, Nanog, and Tbx3. Elucidation of this pathway provides an alternate mechanism by which the primary pluripotency axis may be regulated in vivo and may pave the way for small molecule applications to manipulate pluripotency or improve the efficiency of somatic cell reprogramming.
Wagner
Ryan T
RT
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Xu
Xueping
X
Yi
Fei
F
Merrill
Bradley J
BJ
Cooney
Austin J
AJ
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor; C431936:Nr5a2 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D051176:beta Catenin