Mechanistic Insights into The Role of Microtubule Organizing Centers on Cardiomyocyte Structure and Function

University Of Maryland Baltimore, Baltimore MD

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Abstract

Pediatric dilated cardiomyopathy (DCM) has a poor prognosis, particularly for infants <1-year-old, and the drug development efforts have been hampered by the lack of understanding of disease pathophysiology. While the majority of pediatric DCM cases are considered idiopathic, genetic etiologies are commonly suspected. Against this backdrop, we recently identified the RTTN gene, encoding the centrosome protein Rotatin, as a new causal gene for non-syndromic infantile dilated cardiomyopathy (iDCM). Additionally, we found that impaired centrosome reduction, whereby certain centrosome proteins become “re-localized” to the perinuclear region to form perinuclear microtubule organizing center (pnMTOC), underlies the structural and functional defects observed in the mutant cardiomyocytes. While centrosome reduction has been associated with cell cycle exit in the postnatal heart, this represents the first time in which the defective centrosome reduction/pnMTOC assembly has been specifically linked to DCM in humans. Based on these findings we hypothesize that RTTN is a key regulator of centrosome reduction/pnMTOC formation, required for the formation of proper MT cytoskeleton that governs cardiomyocyte structure and function. To better understand the composition and the functional role of pnMTOC important for proper sarcomere architecture during cardiomyocyte maturation, we will utilize the following two specific aims: 1) Determine the centrosome- associated constituents of the pnMTOC in cardiomyocytes and the mechanism that governs their perinuclear localization during cardiac maturation. 2) Determine the mechanisms by which centrosome reduction and/or pnMTOC governs cardiomyocyte structure and function. The proposed research is highly innovative in that it leverages the newly discovered insights into iDCM pathogenesis to better understand the emerging role of the centrosome as a key regulator of cardiomyocyte structure and function. In doing so, this study will define a novel pathogenic mechanism for pediatric heart failure precipitated by impaired cardiomyocyte maturation and open up new therapeutic opportunities for this devastating disease.