Role of Periostin in Maturation of the Mesenchymal Outflow Tract Septum

Abstract

The critical requirement of the cardiac neural crest (CNC) cells during cardiovascular development is well documented, as are the severe and diverse congenital cardiovascular consequences associated with their removal and/or genetic manipulation. However, the actual role of the CNC in the outflow tract (OFT) itself and what role they play during mesenchymal cushion remodeling and generation of the mature heart remains unclear. Indeed, although the OFT cushions are uniquely colonized by invading CNCs (in contrast to the atrioventricular cushions), it is unclear what function (if any) the CNC play during remodeling and why OFT cushions (future aortic and pulmonary valves) differ from inlet atrioventricular cushions (future mitral and tricuspid valves). Our study of the transcriptional regulation of Periostin (a fasciclin‐family adhesion molecule that is continually expressed throughout cushion formation, remodeling and valvular homeostasis) identified a Periostin 3.9kb transcriptional regulatory module that drives in vivo restricted transient expression in subpopulation of CNC‐derived cells that colonize the distal OFT mesenchymal cushions. Given there are currently no OFT endocardially‐restricted promoters (or even a cushion‐specific promoter), we generated 3.9kb Periostin‐Cre transgenic mice. In combination with R26R reporter and R26‐diptheria toxin‐A genetic ablation mice, we have begun to analyze the role of the 3.9kb Periostin‐expressing OFT subpopulation. Lineage mapping and genetic cell ablation data will be presented. Combined these results indicate that we have identified a unique and powerful molecular tool with which to begin to understand/identify some of the master regulators that control how the OFT mesenchymal cushions are remodeled to give rise to mature heart and what are the molecular differences/origins between the OFT and atrioventricular cushions.