We seek to understand how cell-cell and cell-extracellular matrix interactions contribute to cell shape and polarity within a developing tissue. We apply these biological questions to the development of the nervous system and to the process of myelination, with the goal to translate basic findings into a cure for demyelinating diseases.
Our research focuses on adhesion between myelinating cells, axons and the extracellular matrix and the signals that promote myelination. One of our major efforts has been the study of laminin receptors on Schwann cells, the myelinating peripheral glia. By generating and comparing animal models of demyelinating neuropathies to patient's biopsies, we and others have determined that laminins are required for 'radial sorting' of axons in early development. Radial axonal sorting is a pre-requisite for myelination and is arrested in human laminins and dystroglycan-glycosyltransferases deficiencies. Using conditional mutagenesis we have determined that integrins, dystroglycan and RhoGTPAses are required for radial sorting because they induce cytoskeletal rearrangements that allow the generation of glial extensions that contact and wrap axons.
More recently, we have adapted innovative sub-fractionation and proteomic techniques to profile the extensions contacting axons and the RhoGTPAse interactome in Schwann cells. By these techniques we have identified novel molecules important for myelination and for the support of axons by glial cells. We have recently discovered that mechanical forces generated by the extracellular matrix and other cells are also essential for correct myelination, and we are actively pursuing the molecular mechanisms by which mechanical signals are transduced in myelin-forming glia.
Laminin receptors are also important for myelin and nodes of Ranvier to achieve the correct length, thickness, architecture and stability. Patients lacking laminins have abnormally thick and instable myelin, short internodes and immature nodes of Ranvier. We first determined that laminin 211, dystroglycan and certain integrins are required to form myelin of normal cytoarchitecture, and now we are seeking to understand why perturbing laminin function leads to myelin instability and demyelination.
Using genetic, cell biology and biochemistry we are testing the hypothesis that laminin receptors influence growth factors and signaling molecules to prevent demyelination. These studies also lead us to discover that some of the signaling molecules under scrutiny are more important in the central nervous system, where they inhibit oligodendrocyte myelination. Thus, they represent potential molecular targets to promote remyelination in demyelinating disease such as Multiple Sclerosis of Leukodystrophies.
Since our arrival at the HJKRI we are applying our experience on conditional mutagenesis to ask if there is cell autonomy in the pathogenesis of Krabbe disease.
Dr. Feltri is currently Professor of Biochemistry and Neurology at the Hunter James Kelly Research Institute in the State University of New York at Buffalo. Before 2011 she was the Head of the Unit of NeuroGlia in the San Raffaele Scientific Institute of Milano, and adjunct Associate Professor in the Department of Neurology at the University of Pennsylvania.
View all of Dr. Feltri’s publications on PubMed.