Isoform switch of T-cell factor7L2 during mouse heart development
Canonical WNT signaling plays critical, often opposing roles in heart development and disease, but its context-dependent mechanisms remain unclear. We hypothesized that alternative splicing of Tcf7l2, a key nuclear partner of β-catenin, contributes to WNT signaling specificity in the heart. To inves...
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Elsevier
2025-06-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976125001771 |
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| author | Bo Ye Lu Xiao Yuyong Xu Haodong Xu Faqian Li |
| author_facet | Bo Ye Lu Xiao Yuyong Xu Haodong Xu Faqian Li |
| author_sort | Bo Ye |
| collection | DOAJ |
| description | Canonical WNT signaling plays critical, often opposing roles in heart development and disease, but its context-dependent mechanisms remain unclear. We hypothesized that alternative splicing of Tcf7l2, a key nuclear partner of β-catenin, contributes to WNT signaling specificity in the heart. To investigate this, we cloned and sequenced 53 Tcf7l2 transcripts in ventricular tissues from embryonic day 17.5 (E17.5, 24/53) and postnatal day 8 (P8, 29/53) mice, identifying 32 distinct isoforms. Among 18 potential exons, exons 6 and 17 were absent, and over 80 % of transcripts lacked exon 4. Alternative splicing was prominent in the C-terminal exons (14, 15, and 16), with exon 14 inclusion significantly higher in P8 hearts (64.3 %) than E17.5 hearts (34.8 %). Variations in exon 15 and 16 combinations, along with reading frame shifts caused by the adenine insertion and deletion (indel) near the beginning of exon 18, affected C-terminal structures, altering the presence of the E-tail, C-clamp, and CtBP-binding motifs. Notably, exon 14 insertion introduced a redox-switch domain spanning the NLS and C-clamp regions in E and S isoforms, while adenine indels altered isoform lengths, driving transitions between E, S, and M isoforms. RT-PCR validation across multiple developmental stages confirmed these splicing patterns. Our findings suggest that a postnatal redox-sensitive isoform switch in Tcf7l2 modulates WNT signaling, potentially influencing cardiomyocyte maturation during the transition from proliferation to hypertrophy. |
| format | Article |
| id | doaj-art-6262d2ee28fc407192dc64eb17f043fb |
| institution | OA Journals |
| issn | 2772-9761 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-6262d2ee28fc407192dc64eb17f043fb2025-08-20T02:06:20ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612025-06-011210045810.1016/j.jmccpl.2025.100458Isoform switch of T-cell factor7L2 during mouse heart developmentBo Ye0Lu Xiao1Yuyong Xu2Haodong Xu3Faqian Li4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; Lillehei Heart Institute, Cancer & Cardiovascular Research Center, Minneapolis, MN 55455, USA; Correspondence to: B. Ye, Lillehei Heart Institute, Cancer & Cardiovascular Research Center, 2231 6th Street SE, Minneapolis, MN 55455, USA.Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, MA 02111, USADepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USADepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; Lillehei Heart Institute, Cancer & Cardiovascular Research Center, Minneapolis, MN 55455, USA; Department of Pathology & Laboratory Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, USA; Correspondence to: F. Li, Mail Code 7750, Department of Pathology & Laboratory Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.Canonical WNT signaling plays critical, often opposing roles in heart development and disease, but its context-dependent mechanisms remain unclear. We hypothesized that alternative splicing of Tcf7l2, a key nuclear partner of β-catenin, contributes to WNT signaling specificity in the heart. To investigate this, we cloned and sequenced 53 Tcf7l2 transcripts in ventricular tissues from embryonic day 17.5 (E17.5, 24/53) and postnatal day 8 (P8, 29/53) mice, identifying 32 distinct isoforms. Among 18 potential exons, exons 6 and 17 were absent, and over 80 % of transcripts lacked exon 4. Alternative splicing was prominent in the C-terminal exons (14, 15, and 16), with exon 14 inclusion significantly higher in P8 hearts (64.3 %) than E17.5 hearts (34.8 %). Variations in exon 15 and 16 combinations, along with reading frame shifts caused by the adenine insertion and deletion (indel) near the beginning of exon 18, affected C-terminal structures, altering the presence of the E-tail, C-clamp, and CtBP-binding motifs. Notably, exon 14 insertion introduced a redox-switch domain spanning the NLS and C-clamp regions in E and S isoforms, while adenine indels altered isoform lengths, driving transitions between E, S, and M isoforms. RT-PCR validation across multiple developmental stages confirmed these splicing patterns. Our findings suggest that a postnatal redox-sensitive isoform switch in Tcf7l2 modulates WNT signaling, potentially influencing cardiomyocyte maturation during the transition from proliferation to hypertrophy.http://www.sciencedirect.com/science/article/pii/S2772976125001771Tcf7l2Heart developmentIsoformAlternative splicing |
| spellingShingle | Bo Ye Lu Xiao Yuyong Xu Haodong Xu Faqian Li Isoform switch of T-cell factor7L2 during mouse heart development Journal of Molecular and Cellular Cardiology Plus Tcf7l2 Heart development Isoform Alternative splicing |
| title | Isoform switch of T-cell factor7L2 during mouse heart development |
| title_full | Isoform switch of T-cell factor7L2 during mouse heart development |
| title_fullStr | Isoform switch of T-cell factor7L2 during mouse heart development |
| title_full_unstemmed | Isoform switch of T-cell factor7L2 during mouse heart development |
| title_short | Isoform switch of T-cell factor7L2 during mouse heart development |
| title_sort | isoform switch of t cell factor7l2 during mouse heart development |
| topic | Tcf7l2 Heart development Isoform Alternative splicing |
| url | http://www.sciencedirect.com/science/article/pii/S2772976125001771 |
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