Abstract 575: Primary Cilia of Cardiac Neural Crest Cells Orchestrate Multiple Aspects of Cardiovascular Development

Abstract

Cardiac neural crest cells (CNCC) are a specialized population of migratory neural crest cells that contribute to the developing cardiac outflow tract (OFT) and endocardial cushions (ECC). Like many eukaryotic cells, CNCC also possess primary cilia, which function as membrane-bound sensory organelles involved in intra- and extra-cellular communications in developing tissues. Previous work in our laboratory has shown that primary cilia of cardiac progenitor populations are critical orchestrators of both the septation and alignment of the developing OFT and interventricular septum. Our current in vivo models have refined the elimination of primary cilia to CNCC of the embryonic mouse heart using multiple neural crest-specific Cre drivers ( Wnt1 :Cre-Danielian et al,1998; Wnt1 :Cre2-Soriano et al, 2013) crossed with the Ift88 flox/flox mouse (Haycraft et al, 2007), resulting in elimination of primary cilia from CNCC during early embryonic heart development. Additionally, we have utilized a Td-Tomato (Tdt) reporter mouse line to track the migration of CNCC during various embryonic timepoints. Use of this reporter line revealed transient Tdt-positive CNCC contributions to the ventricular portion of the developing myocardium, in addition to the expected CNCC contributions to in the OFT and ECC regions. The resultant mutant phenotypes included a high incidence of outflow tract defects, impaired septation of the membranous interventricular septum, non-compaction of the developing ventricular myocardium, and perinatal lethality. Our data combine various immunohistochemical approaches to document, characterize, and quantify the novel presence of CNCC in the developing embryonic ventricular myocardium. These data suggest a potential modulatory role for primary cilia of CNCC in the development and maturation of the ventricular myocardium. Primary cilia-mediated signal transduction events that could account for the descried phenotypes are currently being elucidated.