title: Tbx1 modulates endodermal and mesodermal differentiation from mouse induced pluripotent stem cells.
abstract: The T-box transcriptional factor (Tbx) family of transcriptional factors has distinct roles in a wide range of embryonic differentiation or response pathways. Tbx1, a T-box transcription factor, is an important gene for the human congenital disorder 22q11.2 deletion syndrome. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem-cell-based therapies. In this study, we generated iPSCs from Tbx1(-/-) and Tbx1(+/+) fibroblasts and investigated the spontaneous differentiation potential of iPSCs by detailed lineage analysis of the iPSC-derived embryoid bodies. Undifferentiated Tbx1(-/-) and Tbx1(+/+) iPSCs showed similar expression levels of pluripotent markers. The ability of the Tbx1(-/-) iPSCs to generate endodermal and mesodermal lineages was compromised upon spontaneous differentiation into embryonic bodies. Restoration of Tbx1 expression in the Tbx1(-/-) iPSCs to normal levels using an inducible lentiviral system rescued these cells from the potential of defective differentiation. Interestingly, overexpression of Tbx1 in the Tbx1(-/-) iPSCs to higher levels than in the Tbx1(+/+) iPSCs again led to a defective differentiation potential. Additionally, we observed that expression of fibroblast growth factor (FGF) 10 and FGF8 was downregulated in the Tbx1(-/-) iPSC-derived cells, which suggests that Tbx1 regulates the expression of FGFs. Taken together, our results implicated the Tbx1 level as an important determinant of endodermal and mesodermal lineage differentiation during embryonic development.
authors.affiliation: 1 Department of Allied Health Sciences, University of Connecticut , Storrs, Connecticut.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yan
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.forename: Yinhong
authors.initials: Y
authors.lastname: Song
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Xiuchun Cindy
authors.initials: XC
authors.lastname: Tian
authors.forename: Debra
authors.initials: D
authors.lastname: Rood
authors.forename: Laijun
authors.initials: L
authors.lastname: Lai
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D047108:Embryonic Development; D004707:Endoderm / Q000166:cytology*; D051526:Fibroblast Growth Factor 10 / Q000502:physiology; D051524:Fibroblast Growth Factor 8 / Q000502:physiology; D015870:Gene Expression; D055786:Gene Knockout Techniques; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D020825:T-Box Domain Proteins / Q000502:physiology*
chemical_list: C496464:Fgf10 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051524:Fibroblast Growth Factor 8