title: EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells.
abstract: Although human induced pluripotent stem cells (hiPSCs) hold great potential for the study of human diseases affecting disparate cell types, they have been underutilized in seeking mechanistic insights into the pathogenesis of congenital craniofacial disorders. Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by mutations in EFNB1 and characterized by craniofacial, skeletal, and neurological anomalies. Heterozygous females are more severely affected than hemizygous males, a phenomenon termed cellular interference that involves mosaicism for EPHRIN-B1 function. Although the mechanistic basis for cellular interference in CFNS has been hypothesized to involve Eph/ephrin-mediated cell segregation, no direct evidence for this has been demonstrated. Here, by generating hiPSCs from CFNS patients, we demonstrate that mosaicism for EPHRIN-B1 expression induced by random X inactivation in heterozygous females results in robust cell segregation in human neuroepithelial cells, thus supplying experimental evidence that Eph/ephrin-mediated cell segregation is relevant to pathogenesis in human CFNS patients.
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Terren K
authors.initials: TK
authors.lastname: Niethamer
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Larson
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Audrey K
authors.initials: AK
authors.lastname: O'Neill
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bershteyn
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Pomerantz
authors.affiliation: Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeffrey.bush@ucsf.edu.
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Bush
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D065150:Cellular Reprogramming; D041321:Chromosomes, Human, X; D019465:Craniofacial Abnormalities / Q000235:genetics*; D036387:Ephrin-B1 / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009030:Mosaicism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D046569:Neuroepithelial Cells / Q000166:cytology / Q000378:metabolism*; D049951:X Chromosome Inactivation
chemical_list: D036387:Ephrin-B1
keywords: EFNB1; Eph/ephrin signaling; X chromosome inactivation (XCI); cell segregation; cell sorting; craniofacial; craniofrontonasal syndrome (CFNS); human induced pluripotent stem cells (hiPSCs); neural progenitor cells; neuroepithelial cells