Activation of Nkx2.5 Transcriptional Program is Required for Adult Myocardial Repair

We show that cardiac-specific RNA-sequencing studies reveal a disrupted embryonic Nkx2.5 transcriptional profile despite histologically normal, Nkx2.5 loss-of-function adult myocardium. Yet, adult nkx2.5-/- fish exhibit an impaired ability to recover following ventricular apex amputation as illustrated by retention of fibrin and collagen in the injured area. Complex network analyses illuminate that Nkx2.5 is required to mount a proliferative response for cardiomyocyte renewal and to provoke proteolytic pathways necessary for sarcomere disassembly. Moreover, direct Nkx2.5 targets embedded in these distinct gene regulatory modules coordinate appropriate, multi-faceted injury responses. Altogether, our findings support a previously unrecognized, Nkx2.5-dependent regenerative circuit that invokes myocardial proliferation and dedifferentiation to ensure effective regeneration in the teleost heart. Overall design: We harnessed both new RNA-Seq and our prior DamID data to reveal that the developmental molecular profile regulated by Nkx2.5 is perturbed in the adult nkx2.5-deficient myocardium. Moreover, our multi-variate network analysis underlines Nkx2.5 as a vital regulator of CM renewal, functioning to promote cell cycle re-entry and to maintain proteolysis genetic modules.