News and Publications

Regulation of CNS Development and Function by Cell Recognition Molecules

A disproportionately large number of genes in the genomes of vertebrates encode cell recognition molecules that mediate cell-cell interactions and interactions between cells and the extracellular matrix. This finding most likely reflects an evolutionary trend toward increasingly more complex cellular interactions in higher metazoans. The highest diversity of such interactions occurs in the CNS, where thousands of different neuronal subtypes are connected into defined neuronal circuits. We use mouse genetics, genomics, cell biology, biochemistry, and imaging technology to analyze the function of cell recognition molecules in the CNS in developing and adult mice. In another project, we are elucidating the mechanisms by which cell recognition molecules contribute to mechanosensory perception.

Integrin Functions In the CNS

The establishment of the 3-dimensional cytoarchitecture of the nervous system depends on interactions of receptors on neuronal cells with molecules presented within the extracellular matrix and by neighboring cells. Integrins are a class of neuronal receptors that mediate interactions with glycoproteins secreted by the extracellular matrix and with membrane-anchored counterreceptors. Originally identified as adhesion-promoting molecules, integrins were anticipated to have a rather static role, providing a mechanical link between extracellular ligands and the interior of the cell. It is now clear that integrins also have active roles in signal transduction. We analyzed integrin functions in the CNS genetically in mice by using both conventional and conditional gene inactivation.

Our data indicate that integrins have important functions in the formation of the cerebral and cerebellar cortex. The cortical defects in integrin-deficient mice resemble pathologic changes observed in humans who have lissencephaly, Walker-Warburg syndrome, and muscle-brain-eye disease. These abnormalities are associated with peripheral neuropathy and muscular dystrophy. Our recent results in mice indicated that development of peripheral nerve and muscle is also regulated by integrins, suggesting that defects in interactions between cells and the extracellular matrix are at the core of the pathologic changes in humans. We are investigating the integrin-dependent signaling mechanisms important for CNS development and functional interactions of integrins with other receptors and secreted signaling molecules in the CNS.

Cell Recognition Molecules, Mechanosensory Perception, and Usher Syndrome

Mechanosensation, the transduction of mechanical force into an electrochemical signal, allows living organisms to detect touch and sound, register movement and gravity, and sense changes in cell volume and shape. In mammals, the hair cells of the inner ear are the principal mechanosensors for the detection of sound and movement. Hair cells elaborate stereocilia that contain mechanosensitive ion channels. The stereocilia of a hair cell are interconnected by extracellular bridges into a bundle and are situated next to specialized extracellular matrix assemblies. Sound waves or head movements lead to deflection of the stereociliary bundle, changes in the ion permeability of the mechanosensitive channels, and depolarization of the hair cells. The molecules that regulate development and function of hair cells are poorly defined.

Because defects in hair cells cause inherited forms of deafness, we use human and mouse genetics as a guideline to identify and study molecules that regulate the development and function of mechanosensory hair cells. Currently, about 50 genes have been identified in which mutations lead to deafness. Many of these genes encode membrane-anchored cell recognition molecules and secreted extracellular matrix glycoproteins. Mutations in the putative gene for the cell adhesion molecule cadherin 23 lead to Usher syndrome, the leading cause of deaf-blindness in humans. Mice with mutations in the gene for this adhesion molecule have stereociliary defects, suggesting that cadherin 23 regulates the function of stereocilia. We are studying the mechanism of action of cadherin 23 and the function of several other proteins in hair cells and mechanotransduction.

Publications

Feltri, M.L., Graus Porta, D., Previtali, S.C., Nodari, A., Migliavacca, B., Cassetti, A., Littlewood-Evans, A., Reichardt, L.F., Messing, A., Quattrini, A., Müller, U., Wrabetz, L. Conditional disruption of ß₁ integrin in Schwann cells impedes interactions with axons. J. Cell Biol. 156:199, 2002.

Förster, E., Tielsch, A., Saum, B., Weiss, K.H., Johanssen, C., Graus-Porta, D., Müller, U., Frotscher, M. Reelin, Disabled 1, and ß₁-class integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc. Natl. Acad. Sci. U. S. A. 99:13178, 2002.

Hartner, A., Cordasic, N., Klanke, B., Müller, U., Sterzel, R.B., Hilgers, K.F. The α₈ integrin chain affords mechanical stability to the glomerular capillary tuft in hypertensive glomerular disease. Am. J. Pathol. 160:861, 2002.

Leu, M., Bellmunt, E., Schwander, M., Farinas, I., Brenner, H.R., Müller, U. ErbB2 regulates neuromuscular synapse formation and is essential for muscle spindle development. Development 130:2291, 2003.

Müller, U. Cell adhesion molecules and human disorder. In: Encyclopedia of the Human Genome. Cooper, D.N., Thomas, N. (Eds.). Nature Publishing Group, New York, in press.

Schwander, M., Leu, M., Stumm, M., Dorchies, O.M., Ruegg, U.T., Schittny, J., Müller, U. ß₁-Integrins regulate myoblast fusion and sarcomere assembly. Dev. Cell 4:673, 2003.

Siemens, J., Kazmierczak, P., Reynolds, A., Sticker, M., Littlewood-Evans, A., Müller, U. The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions. Proc. Natl. Acad. Sci. U. S. A. 99:14946, 2002.