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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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976125001771 |
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| Summary: | 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. |
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| ISSN: | 2772-9761 |