Abstract 18348: Hoxb13 is a Meis1 Cofactor Involved in Transcriptional Regulation of Cardiomyocyte Cell Cycle

Abstract

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, numerous attempts at unraveling the regenerative potential of the mammalian heart have been pursued to reawaken this process in adult humans. We recently showed that mice are capable of regenerating their hearts shortly after birth following various types of injury. This remarkable regenerative potential appears to be primarily mediated by proliferation of preexisting cardiomyocytes during a brief window of time after birth. However, following arrest of cardiomyocyte proliferation shortly after birth, the mammalian heart loses this regenerative ability. We recently identified Meis1 is a key regulator of postnatal cardiomyocyte cell cycle arrest, where Meis1 deletion in cardiomyocytes results in reactivation of myocyte proliferation in the post-natal heart. However, further the transcriptional networks involved in mediating the postnatal effect of Meis1 in cardiomyocytes remain unclear. The transcriptional activity of Meis1 is known to be tightly linked to a number of Hox genes in various tissues. Therefore, we profiled the expression patterns of entire Hox family of transcription factors by qRT-PCR in the early neonatal window. We found that the only up regulated Hox genes were Hoxa10, Hoxa11, Hoxb13 and Hoxd12, which belonged to the AbdB-like paralogue of Hox genes. Intriguingly, these four transcription factors along with Hoxa9 are the only Hox proteins (out of 37 known mammalian Hox transcription factors) known to interact with Meis1. Detailed analysis of these Hox genes revealed that Hoxb13 mirrors Meis1 expression pattern during normal post-natal development and following injury, shares common cell cycle targets with Meis1, and appears to compensate for loss of Meis1 following its knockout. These findings identify Hoxb13 as a Meis1 cofactor in cardiomyocytes, and an important transcriptional regulator of cardiomyocyte cell cycle.