CMV-induced embryonic mouse organ of Corti dysplasia: network architecture of dysfunctional lateral inhibition

Background Congenital cytomegalovirus infection is the major nongenetic cause of sensorineural hearing loss at birth and beyond. Among other pathologies, there is a striking dysplasia/hyperplasia of organ of Corti hair and supporting cells. Methods Using an in vitro embryonic mouse model of cytomegalovirus-induced cochlear teratogenesis that mimics the known human pathology, and functional signaling network modeling, we tested the hypothesis that cytomegalovirus disrupts the highly ordered organ of Corti hair and supporting cells pattern by dysregulating Notch and Fgfr3, their cognate ligands and downstream effectors. Results Several novel emergent properties of the critical lateral inhibition subnetwork became apparent. The subnetwork has classic small-world properties such as short paths between most gene pairs, few long-distance links, and considerable clustering. Concomitantly, the calculated probability that our specific gene expression dataset is from dysplastic organs of Corti is highly significant (p < 1 × 10−12). Furthermore, we determined that the subnetwork has a highly heterogeneous scale-free topology in which the highly linked genes (hubs), Notch and Fgfr3, play a central role in mediating interactions among the less linked genes. Conclusion This phenomenon has important biologic and therapeutic implications. Birth Defects Research (Part A) 103:573–582, 2015. © 2015 Wiley Periodicals, Inc.