Abstract
The regenerative capacity of the mammalian heart is poor, with one potential reason being that adult cardiomyocytes cannot proliferate at sufficient levels to replace lost tissue. During development and neonatal stages, cardiomyocytes can successfully divide under injury conditions; however, as these cells mature their ability to proliferate is lost. Therefore, understanding the regulatory programs that can induce post-mitotic cardiomyocytes into a proliferative state is essential to enhance cardiac regeneration. Here, we report that the forkhead transcription factor Foxm1 is required for cardiomyocyte proliferation after injury through transcriptional regulation of cell cycle genes. Transcriptomic analysis of injured zebrafish hearts revealed that foxm1 expression is increased in border zone cardiomyocytes. Decreased cardiomyocyte proliferation and expression of cell cycle genes in foxm1 mutant hearts was observed, suggesting it is required for cell cycle checkpoints. Subsequent analysis of a candidate Foxm1 target gene, cenpf, revealed that this microtubule and kinetochore binding protein is also required for cardiac regeneration. Moreover, cenpf mutants show increased cardiomyocyte binucleation. Thus, foxm1 and cenpf are required for cardiomyocytes to complete mitosis during zebrafish cardiac regeneration.
| Original language | English (US) |
|---|---|
| Article number | dev201163 |
| Journal | Development (Cambridge) |
| Volume | 150 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 2023 |
Funding
This research was supported by funding from the National Institutes of Health (R01HL142788 and R01HL156398 to M.T.; R01HL157879 and R01HL159805 to P.V.B.; 1F31HL149148 and T32EB001026 to D.A.Z.). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Open Access funding provided by University of Pittsburgh. Deposited in PMC for immediate release. We are grateful to members of the Tsang lab, Donghun Shin, Andrew Duncan, Bernhard Kuhn and Neil Hukriede for reading the manuscript and experimental suggestions. This research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. This project used the University of Pittsburgh HSCRF Genomics Research Core, RRID: SCR_018301, for RNA-seq experiments. RNA-seq data were analyzed with CLC genomics Workbench Version 20 (QIAGEN), licensed through the Molecular Biology Information Service of the Health Sciences Library System, University of Pittsburgh. This research was supported by funding from the National Institutes of Health (R01HL142788 and R01HL156398 to M.T.; R01HL157879 and R01HL159805 to P.V.B.; 1F31HL149148 and T32EB001026 to D.A.Z.). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Open Access funding provided by University of Pittsburgh. Deposited in PMC for immediate release. We are grateful to members of the Tsang lab, Donghun Shin, Andrew Duncan, Bernhard Kuhn and Neil Hukriede for reading the manuscript and experimental suggestions. This research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. This project used the University of Pittsburgh HSCRF Genomics Research Core, RRID: SCR_018301, for RNA-seq experiments. RNA-seq data were analyzed with CLC genomics Workbench Version 20 (QIAGEN), licensed through the Molecular Biology Information Service of the Health Sciences Library System, University of Pittsburgh.
Keywords
- Binucleation
- Cardiomyocyte proliferation
- Cenpf
- Foxm1
- Heart regeneration
- Zebrafish
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology