Molecular networks of hypoxia and neuronal apoptosis in the cochlea

Abstract

In organotypic cultures, the modiolus (MOD) region of newborn rats shows afourfold higher rate of cell death than the organ of Corti (OC). The differing vulnerability of OC and MOD cells is related to differential expression of numerous genes (DEG). Organotypic cultures of OC and MOD of 3-5-day-old rats were exposed to anormoxic or a hypoxic (pO2 10-20 mmHg; 5 h) atmosphere. Cell death rate and gene expression as detected by c‑DNA microarray analysis were determined 24 h after the culture was created. Genes with modified expression (n = 60) were analyzed for biological processes according to the DAVID Gene Ontology Database (GO). Molecular networks were created using the STRING and ConsensusPathDB databases. The network of the GO annotations "hypoxia", "inflammation", and "mechanical stimulus" indicates the existence of two gene clusters: acluster with pro-inflammatory genes (Ccl3, Cxcl2, Cxcr4, Ccl20) and acluster with hypoxia-associated genes (e.g., c-Jun, Hif1a, and Vegfa). The network of the GO annotations "positive and negative regulation of neuron apoptotic process" suggests that the differential expression of c-Jun, Ngfr, and Casp3 is important for regulation of programmed cell death in neuronal cells of the OC and MOD. While c‑JUN acts as an important modulator of the balance between cell death and survival, the associations of NGFR and CASP3 seem to be significant for the initiation of cell death. The evaluation and application of findings from biostatistical databases is important for understanding the function of individual genes and gene clusters in medically relevant biological processes.