title: A rare human syndrome provides genetic evidence that WNT signaling is required for reprogramming of fibroblasts to induced pluripotent stem cells.
abstract: WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with focal dermal hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram with standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPSCs, whereas daily stimulation with Wnt3a produces FDH-iPSCs with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation and its tight relationship with oncogenic transformation.
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ross
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Busch
authors.affiliation: Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Mintz
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Damian
authors.initials: D
authors.lastname: Ng
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stanley
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Brafman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ignatia
authors.initials: I
authors.lastname: Van den Veyver
authors.affiliation: Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: kwillert@ucsd.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Willert
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D048430:Cell Shape; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000502:physiology*; D005489:Focal Dermal Hypoplasia / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; D014157:Transcription Factors