Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor that is activated by native collagen. The physiological functions of DDR1 include matrix homeostasis and cell growth, adhesion, branching, and migration, but the specific role of DDR1 in the development and function of the inner ear has not been analyzed. Here, we show that deletion of the DDR1 gene in mouse is associated with a severe decrease in auditory function and substantial structural alterations in the inner ear. Immunohistochemical analysis demonstrated DDR1 expression in several locations in the cochlea, mostly associated with basement membrane and fibrillar collagens; in particular in basal cells of the stria vascularis, type III fibrocytes, and cells lining the basilar membrane of the organ of Corti. In the stria vascularis, loss of DDR1 function resulted in altered morphology of the basal cells and accumulation of electron-dense matrix within the strial epithelial layer in conjunction with a focal and progressive deterioration of strial cells. Cell types in proximity to the basilar membrane, such as Claudius', inner and outer sulcus cells, also showed marked ultrastructural alterations. Changes in the organ of Corti, such as deterioration of the supporting cells, specifically the outer hair cells, Deiters', Hensen's and bordering cells, are likely to interfere with mechanical properties of the organ and may be responsible for the hearing loss observed in DDR1-null mice. These findings may also have relevance to the role of DDR1 in other disease processes, for example, those affecting the kidney.

The presence of melanin in the inner ear was established more than a century ago, but the exact biological function of the pigment in the labyrinth has yet to be determined. In this brief review, the correlation of pigmentation and inner ear function, as well as the presumed role of melanocytes in hereditary diseases are discussed. Special attention was drawn to the composition of melanin and its presumed function as a biological reservoir for divalent ions and as an ion exchanger, as well as an intracellular buffering system for calcium. It is pointed out that melanin is capable of binding ototoxic drugs. Finally, morphological responses of melanocytes to local disturbance of Ca++ homeostasis in the inner ear are described as 1) intracellular movement and intraepithelial deposition of melanosomes; 2) cell motility; 3) neomelanogenesis; and 4) enhanced exocytotoxic/endocytotic activity. The possible consequences of this malfunction of the melanocytes on the inner ear function are discussed.

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The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.

The loss of the function of the peroxisomal Mpv17-protein and associated imbalanced radical oxygen species (ROS) homeostasis leads to an early onset of focal segmental glomerulosclerosis and sensorineural deafness associated with severe degeneration of cochlear structures. An excessive enlargement of basal laminae of the stria vascularis capillaries and glomeruli indicates numerous changes in their molecular composition. The basement membrane (BM) of the glomeruli and the stria vascularis are simultaneously affected in early stages of the disease and the lamination, splitting of the membrane and formation of the "basket weaving" seen at the onset of the disease in the kidney are similar to the ultrastructural alterations characteristic for Alporta9s syndrome. The progressive alteration of the BMs is accompanied by irregularity in the distribution of the collagen IV subunits and by an accumulation of the laminin B2(gamma1) in the inner ear and B(beta1) in the kidney. Since Mpv17 protein contributes to ROS homeostasis, further studies are necessary to elucidate downstream signaling molecules activated by ROS. These studies explain the cellular responses to missing Mpv17-protein, such as accumulation of the extracellular matrix, degeneration, and apoptosis in the inner ear.