DISSOCIATED SPATIAL PATTERNING OF GAP-JUNCTIONS AND CELL-ADHESION JUNCTIONS DURING POSTNATAL DIFFERENTIATION OF VENTRICULAR MYOCARDIUM

Nonuniformity in the spatial patterning of gap junctions between heart muscle cells is now recognized as an important determinant of electro mechanical function in working myocardium. Breakdown of the normal geo metry of electrical intercellular connectivity in diseased myocardium correlates with reentry, arrhythmia, and conduction disturbance. The d evelopmental mechanism(s) that determines this precise spatial order i n gap junction organization in normal myocardium is at present unknown . To examine this question, we have used immunoelectron and immunoconf ocal microscopy to analyze the spatial distributions of gap junctional (connexin43), desmosomal (desmoplakin), and adherens junctional (N-ca dherin) components during maturation of rodent and canine left ventric ular myocardium. In rats, a striking divergence in the distribution of gap junctions and cell adhesion junctions emerged within the first 20 days of postnatal life. It was found that although gap junctions init ially demonstrated dispersed distributions across myocyte cell membran es, desmosomes and adherens junctions showed more rapid polarization t oward cell termini tie, nascent intercalated disks) after birth. Over subsequent postnatal development (20 to 90 postnatal days), gap juncti ons became progressively concentrated in these cell adhesion junction- rich zones of membrane. Quantitative analyses of this process in a ser ies of rats aged 15 embryonic and 1, 5, 10, 20, 40, 70, and 90 postnat al days indicated that significantly higher levels (P<.01) of N-cadher in and desmoplakin than of connexin43 were immunolocalized to cell ter mini by as early as postnatal day 5. Although all three junctions type s showed increasing polarization to myocyte termini with development, variation between junctions remained significant (P<.05) at all times points between 5 and 70 postnatal days. Only at 90 postnatal days, whe n the animals were nearly full grown, did the proportions of gap junct ion, desmosome, and adherens junction at intercalated disks become sta tistically similar (P>.05). Examination of myocardium from 1- and 3-mo nth-old canines revealed that related differential changes to the spat iotemporal distribution of intercellular junctions occurred during pos tnatal maturation of the dog heart, suggesting that the process was no t rodent specific. It is concluded that this progressive change in the organization and pattern of association between gap junctions and cel l adhesion junctions is likely to be an important factor in maturation of electromechanical function within the mammalian heart.