Title : A novel role for microcephaly - Associated scaffold protein WDR62 in postnatal cardiac physiology
Abstract:
Cardiovascular diseases are the leading causes of death worldwide. The proliferative capability of the contractile cells of the heart (cardiomyocytes), decreases after birth and damage to mature cardiomyocytes result in fibrotic scar formation driven by cardiac fibroblasts and differentiated myofibroblasts. Primary cilia are non-motile organelles that sense mechanical stretch and translate these stimuli to regulate cell signalling. A microcephaly-associated scaffolding protein called WD-repeat protein 42 (WDR62), has been shown to be important to both cell-cycle progression and primary cilia formation, however little is known about the role of this protein in cardiac cell types in normal and pathological states. We therefore aimed to 1) assess the role of WDR62 in cardiomyocyte proliferation and postnatal growth; 2) characterise primary ciliation changes during maturation and 3) evaluate changes in primary cilia in three models of cardiac stress. We administered an adeno-associated virus (AAV) driving expression Cre-recombinase to P1 WDR62 floxed and wild-type neonates (P1). Reduced WDR62 expression was co-incident with decreased cardiomyocyte proliferation and reduced heart weight at P56, without modification of heart function. Immunohistochemistry was used to determine the number and location of primary cilia in neonatal (P1) and adult (P56) hearts with primary cilia present on both cardiomyocytes, fibroblasts and endothelial cells in neonatal mice, but apparently absent in adult cardiomyocytes. Heart sections from adult (wildtype) hearts undergoing remodelling induced by Angiotensin II, myocardial infarction and exercise were assessed for primary ciliation, with only myocardial infarction increasing primary ciliation number. Thus, WDR62 is essential to cardiac enlargement in neonatal mice, and primary cilia on cardiac fibroblasts may be important to remodelling following myocardial infarct.
