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XB-ART-54948
Stem Cells September 1, 2018; 36 (9): 1368-1379.

Serine Threonine Kinase Receptor-Associated Protein Deficiency Impairs Mouse Embryonic Stem Cells Lineage Commitment Through CYP26A1-Mediated Retinoic Acid Homeostasis.

Jin L , Chang C , Pawlik KM , Datta A , Johnson LM , Vu T , Napoli JL , Datta PK .


Abstract
Retinoic acid (RA) signaling is essential for the differentiation of embryonic stem cells (ESCs) and vertebrate development. RA biosynthesis and metabolism are controlled by a series of enzymes, but the molecular regulators of these enzymes remain largely obscure. In this study, we investigated the functional role of the WD-domain protein STRAP (serine threonine kinase receptor-associated protein) in the pluripotency and lineage commitment of murine ESCs. We generated Strap knockout (KO) mouse ESCs and subjected them to spontaneous differentiation. We observed that, despite the unchanged characteristics of ESCs, Strap KO ESCs exhibited defects for lineage differentiation. Signature gene expression analyses revealed that Strap deletion attenuated intracellular RA signaling in embryoid bodies (EBs), and exogenous RA significantly rescued this deficiency. Moreover, loss of Strap selectively induced Cyp26A1 expression in mouse EBs, suggesting a potential role of STRAP in RA signaling. Mechanistically, we identified putative Krüppel-like factor 9 (KLF9) binding motifs to be critical in the enhancement of non-canonical RA-induced transactivation of Cyp26A1. Increased KLF9 expression in the absence of STRAP is partially responsible for Cyp26A1 induction. Interestingly, STRAP knockdown in Xenopus embryos influenced anterior-posterior neural patterning and impaired the body axis and eye development during early Xenopus embryogenesis. Taken together, our study reveals an intrinsic role for STRAP in the regulation of RA signaling and provides new molecular insights for ESC fate determination. Stem Cells 2018;36:1368-1379.

PubMed ID: 29781215
Article link: Stem Cells
Grant support: [+]
Genes referenced: crabp1 cyp26a1 egr2 en2 gata4 gata6 hoxa10 hoxb1 hoxb9 hoxd4 igf2 klf9 lif mef2c myod1 nes npat otx2 pax3 pax6 pou5f3.1 rarb sox17a sox17b.1 sox17b.2 sp1 stra6 stra8 strap twist1 vim vim.2
GO keywords: stem cell differentiation
Morpholinos: strap MO1


Article Images: [+] show captions


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