Evolution and development of ventricular septation in the amniote heart

PLoS One. 2014 Sep 5;9(9):e106569. doi: 10.1371/journal.pone.0106569. eCollection 2014.


During cardiogenesis the epicardium, covering the surface of the myocardial tube, has been ascribed several functions essential for normal heart development of vertebrates from lampreys to mammals. We investigated a novel function of the epicardium in ventricular development in species with partial and complete septation. These species include reptiles, birds and mammals. Adult turtles, lizards and snakes have a complex ventricle with three cava, partially separated by the horizontal and vertical septa. The crocodilians, birds and mammals with origins some 100 million years apart, however, have a left and right ventricle that are completely separated, being a clear example of convergent evolution. In specific embryonic stages these species show similarities in development, prompting us to investigate the mechanisms underlying epicardial involvement. The primitive ventricle of early embryos becomes septated by folding and fusion of the anterior ventricular wall, trapping epicardium in its core. This folding septum develops as the horizontal septum in reptiles and the anterior part of the interventricular septum in the other taxa. The mechanism of folding is confirmed using DiI tattoos of the ventricular surface. Trapping of epicardium-derived cells is studied by transplanting embryonic quail pro-epicardial organ into chicken hosts. The effect of decreased epicardium involvement is studied in knock-out mice, and pro-epicardium ablated chicken, resulting in diminished and even absent septum formation. Proper folding followed by diminished ventricular fusion may explain the deep interventricular cleft observed in elephants. The vertical septum, although indistinct in most reptiles except in crocodilians and pythonidsis apparently homologous to the inlet septum. Eventually the various septal components merge to form the completely septated heart. In our attempt to discover homologies between the various septum components we aim to elucidate the evolution and development of this part of the vertebrate heart as well as understand the etiology of septal defects in human congenital heart malformations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chick Embryo
  • Elephants
  • Heart / anatomy & histology
  • Heart / embryology*
  • Heart Septum / anatomy & histology
  • Heart Septum / embryology*
  • Heart Septum / metabolism
  • Humans
  • Mice
  • Organogenesis / physiology*
  • Pericardium / cytology
  • Pericardium / embryology
  • Pericardium / metabolism
  • Reptiles
  • T-Box Domain Proteins / metabolism


  • T-Box Domain Proteins
  • T-box transcription factor 5

Grants and funding

B.J. is supported by The Danish Council for Independent Research Natural|Sciences. B.P.T.K. is supported by the Netherlands Institute for Regenerative Medicine and the BioMedical Materials Institute, M.K.R. is supported by AgentschapNL, Smartmix SSM06010, R.V.-S. receives support from the Netherlands Heart Foundation, 2012T71. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.