Fkbp 1 a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch 1 activity

INTRODUCTION The formation of the ventricular walls is essential to cardiogenesis and is required for normal cardiac function (Moorman and Christoffels, 2003). Ventricular trabeculation and compaction are important morphogenetic events that are controlled by a precise balance between cardiomyocyte proliferation and differentiation during ventricular chamber formation and wall maturation. The trabeculation phase of cardiac development is initiated at the end of cardiac looping (E9.0 to E9.5 in mouse) and is defined as the growth of primitive cardiomyocytes to form the highly organized muscular ridges that are lined by layers of invaginated endocardial cells (Ben-Shachar et al., 1985). The newly formed trabeculae gradually contribute to the formation of the papillary muscles, the interventricular septum and cardiac conductive cells. Concomitant with ventricular septation, the trabeculae start to compact at their base adjacent to the outer myocardium, adding substantially to ventricular wall thickness and coincidently establishing coronary circulation (Wessels and Sedmera, 2003). A significant reduction in trabeculation is closely associated with myocardial growth arrest, whereas persistent trabeculation and/or a reduced level of compaction are associated with left ventricular noncompaction (LVNC) (Towbin, 2010) [also called left ventricular hypertrabeculation (LVHT)] (Finsterer, 2009). LVNC (MIM300183) is a distinct form of inherited cardiomyopathy (Pignatelli et al., 2003; Sandhu et al., 2008). Although some LVNC patients survive into adulthood (Weiford et al., 2004), severe cases accompanied with other cardiac defects (e.g. Ebstein’s anomaly) commonly die at a young age (Koh et al., 2009). The underlying molecular and cellular mechanisms that orchestrate ventricular trabeculation and compaction, as well as the pathogenesis of LVNC, are poorly understood due to the heterogeneity of the patients and the lack of suitable genetic models (Srivastava and Olson, 2000). Genetic screening of isolated LVNC patients has identified a handful of gene mutations in sarcomere proteins (Klaassen et al., 2008; Xing et al., 2006). However, the genes that are linked to the more severe cases of pediatric LVNC have yet to be identified. Previously, we showed that mutant mice deficient in FK506 binding protein 1a (Fkbp1a, also known as FKBP12) develop multiple abnormal cardiac structures that phenocopy severe cases of LVNC, including a characteristic increase in the number and thickness of ventricular trabeculae (i.e. hypertrabeculation), deep intertrabecular recesses, lack of compaction that leads to a thin left ventricular wall (i.e. noncompaction) and a prominent ventricular septal defect (VSD) (Shou et al., 1998). Fkbp1a is a ubiquitously expressed 12 kDa peptidyl-prolyl isomerase (Bierer et al., 1990; Schreiber and Crabtree, 1995). It binds to FK506 and rapamycin and inhibits calcineurin and mTOR activity. Fkbp1a is associated with multiple intracellular protein 1Riley Heart Research Center, Division of Pediatric Cardiology and 2Division of Neonatology, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 3Department of Pediatric Cardiac Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, China. 4Department of Pharmacology, Harbin Medical University, Harbin 150081, China. 5Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. 6The Heart Institute, Division of Pediatric Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.