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The limited regenerative ability of the adult human heart after injury, however, poses a significant obstacle to restore cardiac function effectively. While mammalian hearts, including those of mice and humans, do have the potential to regenerate, this capacity is restricted to a narrow window during early stages of life. The molecular mechanisms governing the regenerative capacity of mammalian hearts remain incompletely understood. Exploring a comparative transcriptome analysis in regenerative neonatal vs. non-regenerative adult mouse CMs, we identified N-Cadherin, a member of Ca2+-dependent cell adhesion protein cadherin superfamily, as a potential novel regulator of CM proliferation/renewal. The primary objectives of this study were to elucidate the molecular mechanisms through which N-Cadherin regulates cardiomyocyte proliferation and regeneration, and to determine the therapeutic potential to promote CM renewal and restore cardiac function following injury by targeting N-Cadherin. Cardiac N-Cadherin expression exhibits a strong positive correlation with that of cell cycle- and proliferation-related genes. Its expression levels show an age-dependent reduction, with a 75% decrease of N-Cadherin in adult, compared to P1 neonatal, CMs. N-Cadherin expression is upregulated in the neonatal mouse heart in response to apical resection, especially in the peri-injury region, coinciding with increased CM mitotic activities in the neonatal heart. Knocking down N-Cadherin reduced, whereas overexpression of N-Cadherin increased, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, increased N-Cadherin potentiates CM renewal through direct binding with and stabilization of a pro-mitotic transcription regulator β-Catenin, leading to increased CMs proliferative activity. Deletion of β-Catenin-binding domain on N-Cadherin abrogated its pro-regenerative activity. Importantly, targeted depletion of N-Cadherin in CMs resulted in incomplete cardiac repair/regeneration and excessive fibrotic scar formation in neonatal mouse hearts following injury. Cardiac-specific overexpression of N-Cadherin in adult mouse heart using adeno-associated viral vectors, by contrast, resulted in increased CM proliferation and protected against myocardial infarction-induced adverse remodeling and contractile dysfunction. Adherent junction protein N-cadherin is demonstrated to play a crucial role in maintaining CM renewal potential by post-translational stabilization of β-Catenin. Enhancing N-cadherin expression levels and downstream signaling activities in the heart, therefore, could be a powerful new approach to promote cardiac regeneration and restore myocardial function in adult human heart following injury. Overall design: To identify mediators of cardiac muscle regeneration, deep RNA sequencing was conducted utilizing isolated ventricular cardiomyocytes from neonatal (on postnatal day 1 & 3 [P1 & P3], both n=4 ) and adult (8-12 weeks, n=7) mice."],"repository":["ENA"],"description_synonyms":["Uvomorulin, Heart, N Cadherin, CDHE, l(3)rK137, P Cadherins, Heart Muscle Cells, Liver Cell Adhesion Molecule, Liver Cell Adhesion Molecules, Myocyte, Cardiac., E-Cadherin, Epithelial-Cadherins, 0763/13, CG17228, Catenin, l(3)10419, 1135/09, Cardiac Muscle, 1135/07, dmTAF8, Cardiac, DmelCG17228, Catenin Protein, HL-VIII, 0451/09, anon-WO0140519.15, F15E12.6, Prosp, CDHN, Muscle Cell, Neural, P-Cadherin, PROS, F15E12_6, 0244/09, 0585/13, MUB3_18, Cadherin 1, Cardiac Myocytes, DROPROSA, Cadherin 3, CG7128, Cadherin 2, MUB3.18, l(3)j6E2, Muscle Cells, l(3)rH013, 671/2, prod, 0320/10, P-Cadherins, Prodos, DMPROSPER, E-Cad|CTF3, Cardiomyocytes, Catenin Proteins, E-Cad|CTF2, E-Cad|CTF1, Cardiac Myocyte, Neural Cadherin, TAF, 0563/18, CD325, CD324, Neural cadherin, single organism signaling, 0671/02, l(3)j12C8, Epithelial cadherin, Placental, CDw325, l(3)rO534, PRO, Pro, Heart Muscle, N-Cadherin, Endogenous, Ncad, CYS, E Cadherin, Cell, l(3)rJ806, Pros, E-Cadherins, l(3)rL433, PROS-1, PROS-2, l(3)rI160, Epithelial-Cadherin, 0441/16, Cadherin, pro, 1316/02, Protein, TFIID, BcDNA:HL08040, Cardiomyocyte, Cadherins, and GLY protein 2, Placental Cadherins, NCAD, MET, ATCMPG1, ATCMPG2, Regenerations, and GLY protein 1, Neural Cadherins, Voila, Cadherin-2, Epithelial Cadherin, Cadherin-1, E-cadherin, N Cadherins, Cadherin-3, UVO, 0664/07, 1167/13, N-cadherin, Cardiac Muscle Cells, TAF[[II]], Cardiac Muscle Cell, P Cadherin, N-Cadherins, l(3)rK204, Heart Muscle Cell, Epithelial Cadherins, CAM 120|80, Endogenous Regeneration, DmelCG7128, signalling process, Cells, Regeneration, l(1)16Fg, TAF8, 0989/01, E Cadherins, pds"],"name_synonyms":["Uvomorulin, Heart, N Cadherin, CDHE, l(3)rK137, P Cadherins, Heart Muscle Cells, Liver Cell Adhesion Molecule, Liver Cell Adhesion Molecules, Myocyte, Cardiac., E-Cadherin, Epithelial-Cadherins, 0763/13, CG17228, Catenin, l(3)10419, 1135/09, Cardiac Muscle, 1135/07, dmTAF8, Cardiac, DmelCG17228, Catenin Protein, HL-VIII, 0451/09, anon-WO0140519.15, F15E12.6, Prosp, CDHN, Muscle Cell, Neural, P-Cadherin, PROS, F15E12_6, 0244/09, 0585/13, MUB3_18, Cadherin 1, Cardiac Myocytes, DROPROSA, Cadherin 3, CG7128, Cadherin 2, MUB3.18, l(3)j6E2, Muscle Cells, l(3)rH013, 671/2, prod, 0320/10, P-Cadherins, Prodos, DMPROSPER, E-Cad|CTF3, Cardiomyocytes, Catenin Proteins, E-Cad|CTF2, E-Cad|CTF1, Cardiac Myocyte, Neural Cadherin, TAF, 0563/18, CD325, CD324, Neural cadherin, single organism signaling, 0671/02, l(3)j12C8, Epithelial cadherin, Placental, CDw325, l(3)rO534, PRO, Pro, Heart Muscle, N-Cadherin, Endogenous, Ncad, CYS, E Cadherin, Cell, l(3)rJ806, Pros, E-Cadherins, l(3)rL433, PROS-1, PROS-2, l(3)rI160, Epithelial-Cadherin, 0441/16, Cadherin, pro, 1316/02, Protein, TFIID, BcDNA:HL08040, Cardiomyocyte, Cadherins, and GLY protein 2, Placental Cadherins, NCAD, MET, ATCMPG1, ATCMPG2, Regenerations, and GLY protein 1, Neural Cadherins, Voila, Cadherin-2, Epithelial Cadherin, Cadherin-1, E-cadherin, N Cadherins, Cadherin-3, UVO, 0664/07, 1167/13, N-cadherin, Cardiac Muscle Cells, TAF[[II]], Cardiac Muscle Cell, P Cadherin, N-Cadherins, l(3)rK204, Heart Muscle Cell, Epithelial Cadherins, CAM 120|80, Endogenous Regeneration, DmelCG7128, signalling process, Cells, Regeneration, l(1)16Fg, TAF8, 0989/01, E Cadherins, pds"],"additional_accession":[]},"is_claimable":false,"name":"N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes","description":"N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes","dates":{"last_updated":"2025-09-24","first_public":"2024-12-12"},"accession":"PRJNA1068015","cross_references":{"GEO":["GSE253966"],"taxon":["10090"],"PubMed":["39837836"]}}