Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1

Abstract

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.

Linkage and association study of discoidin domain receptor 1 as a novel susceptibility gene for childhood IgA nephropathy

“…Even though previous studies contradict our finding (6)(7)(8)(9)(10)21,22), these studies nevertheless suggested that the DDR1 gene participates in the development and progression of diseases, such as, auto-inflammatory and renal diseases.…”

“…DDR1 is a possible susceptibility marker of diseases other than renal diseases, such as schizophrenia, ovarian cancer, juvenile oligoarthritis, hearing loss, Churg-Strauss syndrome, small cell lung carcinoma, and endometrial cancer (6)(7)(8)(9)(10)21,22). Notably, in one study on schizophrenia (9), in which rs1049623 was found to be a susceptibility marker, but this SNP was found to have no significance in the present study.…”

“…Messenger RNA (mRNA) expression of DDR1 is predominantly observed in epithelial cells, particularly those from the kidney, lung, gastrointestinal tract, and brain. However, little is known about the precise cellular distribution of DDR1 protein (1,3,(5)(6)(7)(8)(9)(10). After binding collagen, DDR1 is dimerized, and phosphorylated as tyrosine kinase, which leads to P38MAP/kinase activation, which means that it is the only collagen receptor known to display direct intracellular signaling activity.…”

The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

“…This phenotype was associated with abnormalities of the mammary gland epithelium inducing a deficient lactation process [15] . DDR1 KO mice also exhibited abnormalities in the inner ear architecture leading to impaired audition [17] . In kidney, an initial study reported a thickening of the glomerular basement membrane, which did not affect the renal function, since uremia was at the normal range [13] .…”

Mechanoreception at the cell membrane: More than the integrins

“…A complex between the collagen triple helix and DDR1 functions in mechanotransduction in the inner ear of the mouse auditory system [35]. The ECM rich inner ear provides the mechanical elasticity and rigidity required for the cellular transformation of sound into electrical signals [35][36][37].…”