Extracellular matrix in the brain: roles during development and during neurodegeneration

We study a specialized glial cell, the oligodendrocyte, which myelinates axons in the brain and spinal cord. The laminin family of adhesion proteins are good candidates to regulate oligodendrocytes and the process of myelination: brain defects, including abnormal myelination, occur in the absence of normal laminin signaling. Our work has demonstrated that adhesive interactions with laminins can stimulate oligodendrocytes to survive and differentiate, at least in part by altering interactions with growth factors and downstream signal transduction mechanisms. We are now learning how laminins and laminin-regulated signaling molecules operate during normal brain development and function, as well as during diseases where myelination is dysregulated. An understanding of the mechanisms that control myelination will be important for two areas of human health: (1) during development, where normal myelination is crucial, and (2), during brain and spinal cord repair, which is hampered by the inability of the central nervous system (CNS) to regenerate. Remyelination failure leads to the neurodegeneration in demyelinating diseases such as Multiple Sclerosis, and is predicted to play a role in the neurodegeneration process in diseases such as Alzheimer's, and, following CNS injury in which new neuronal connections need to be myelinated to achieve functional recovery. One of our long-term objectives is to design pharmacological strategies to enhance myelination and myelin repair in the damaged nervous system.

Baron W, Colognato H, ffrench-Constant C. (2005) Integrin-growth factor interactions as regulators of oligodendroglial development and function. Glia. 49(4): 457-593.

ffrench-Constant, C. and Colognato, H. (2004) Integrins: versatile integrators of extracellular signals. Trends in Cell Biol. 14(12):678-686.

Colognato, H., Ramachandrappa, S., Olsen, I.M., and ffrench-Constant, C. Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. (2004) J. Cell Biol. 162(2):365-375.

ffrench-Constant, C., Colognato, H., and Franklin, R.J.M. (2004) The Mysteries of Myelin Unwrapped. Science. 304(5671):688-9

Colognato, H., and ffrench-Constant, C. (2004) Mechanisms of glial development. Curr. Opin. in Neurobiol. 14:37-44.

Baron,W., Decker,L., Colognato,H., and ffrench-Constant,C. (2003) Regulation of integrin growth factor interactions in oligodendrocytes by lipid raft microdomains. Curr. Biol. 13(2):151-155.

Colognato, H., Baron, W., Avellana-Adalid, V., Relvas, J., Baron-van Evercooren, A., Georges-Labouesse, E., and ffrench-Constant,C. (2002) CNS integrins switch growth factor signaling to promote target-dependent survival. Nat. Cell Biol. 4(11):833-841.

Colognato, H., and Yurchenco, P.D. (2000) Form and function: the laminin family of heterotrimers. Dev.Dyn. 18(2):213-234.

Colognato, H., and Yurchenco, P.D. (1999) The laminin a2 expressed by dystrophic dy 2J mice is defective in its ability to form polymers. Curr.Biol. 9(22):1327-1330.

Colognato, H., Winkelmann, D.A., and Yurchenco, P.D. (1999) Laminin polymerization induces a receptor-cytoskeleton network. J. Cell Biol. 145:619-631.

Ivins, J.K., Colognato, H., Kreidberg J.A., Yurchenco, P.D., and Lander, A.D. (1998) Neuronal receptors mediating responses to antibody activated laminin-1 . J Neurosci. 18(23):9703-15.

Colognato, H., MacCarrick, M., O'Rear, J.J., and Yurchenco, P.D. (1997) The laminin a 2-chain short arm mediates cell adhesion through both the a 1 b 1 and a 2 b 1 integrins. J. Biol. Chem . 272:29330-29336.

Yurchenco, P.D., Quan, Y., Colognato, H., Mathus, T., Harrison, D., Yamada, Y., and O'Rear, J.J. (1997) The a chain of laminin-1 is independently secreted and drives secretion of its b - and g -chain partners. Proc. Natl. Acad. Sci. USA. 94:10189-10194.

Allemand, V., Y. Sunada, M.A.M. Salih, V. Straub, C.O. Ozo, M.H.S. Al-Turaiki, M. Akbar, T. Kolo, H. Colognato, X. Zhang, L.M. Sorokin, P.D. Yurchenco, K. Tryggvason and K.P.Campbell. (1997) Mild congenital muscular dystrophy in two patients with an internally deleted laminin a 2-chain. Hum. Mol. Genet . 6:747-752.

Colognato, H., O'Rear, J.J., Yamada, Y., Carbonetto, S., Cheng, Y.-S., and Yurchenco, P.D. (1995) Mapping of network-forming, heparin-binding, and a 1 b 1 integrin-recognition sites within the a -chain short arm of laminin-1. J. Biol. Chem . 270:9398-9406.

Yurchenco, P.D., Cheng, Y.-S., and Colognato, H. (1992) Laminin forms an independent network in basement membranes. J. Cell Biol. 117:1119-1133.