Mice deficient in NCAM-1 exhibited defects in Purkinje cell gene expression, ventricular conduction system patterning, and cardiac conduction disease.
NCAM-1 and its post-translational modification by polysialic acid are essential for the proper development and function of the ventricular conduction system.
The most distal portion of the ventricular conduction system (VCS) contains cardiac Purkinje cells (PCs), which are essential for synchronous activation of the ventricular myocardium. Contactin-2 (CNTN2), a member of the immunoglobulin superfamily of cell adhesion molecules (IgSF-CAMs), was previously identified as a marker of the VCS. Through differential transcriptional profiling, we discovered two additional highly enriched IgSF-CAMs in the VCS: NCAM-1 and ALCAM. Immunofluorescence staining showed dynamic expression patterns for each IgSF-CAM during embryonic and early postnatal stages, but ultimately all three proteins became highly enriched in mature PCs. Mice deficient in NCAM-1, but not CNTN2 or ALCAM, exhibited defects in PC gene expression and VCS patterning, as well as cardiac conduction disease. Moreover, using ST8sia2 and ST8sia4 knockout mice, we show that inhibition of post-translational modification of NCAM-1 by polysialic acid leads to disrupted trafficking of sarcolemmal intercalated disc proteins to junctional membranes and abnormal expansion of the extracellular space between apposing PCs. Taken together, our data provide insights into the complex developmental biology of the ventricular conduction system.
Delgado et al. (Wed,) conducted a other in Ventricular conduction system development. NCAM-1 deficiency vs. Wild-type/control mice was evaluated on Ventricular conduction system patterning and cardiac conduction disease. Mice deficient in NCAM-1 exhibited defects in Purkinje cell gene expression, ventricular conduction system patterning, and cardiac conduction disease.