Laminin mechanisms controlling axonal sorting

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DESCRIPTION (provided by applicant): Our long term goal is to understand the cell and molecular mechanisms that control the growth and differentiation of peripheral nerve glial cells, called Schwann cells. Schwann cells normally proliferate and adopt specific differentiated phenotypes in direct proportion to, and association with, the number and subtype of axons in the nerve. Defects in Schwann cell growth and differentiation are the cause of congenital and acquired neurological disorders, and limit the regenerative capacity of motor and sensory nerves following trauma and/or surgery. This project characterizes signaling pathways that coordinate the proliferation and pro- myelinating differentiation of Schwann cells during the developmental process of "radial axonal sorting", when immature Schwann cells expand, differentiate, and establish mature myelinating or nonmyelinating relationships with axons. We have identified two components of the Schwann cell basal lamina, laminins-211 and -411, which are required for Schwann cells to begin axonal sorting. They have nonredundant activities, implicating separate signaling axes. To test this hypothesis by combining loss-of-function mutations in primary laminin receptors with loss-of-function mutations in laminin-2 and laminin-8. We predict distinct defects in the ability of Schwann cells to proliferate and/or differentiate will result in specific mutant combinations, thereby establishing the identity of the putative signaling axes. Quantitative and immunochemical methods will be used to characterize Schwann cell development across the mutant combinations. By identifying the signaling pathways that choreograph neuron:glia interactions in developing nerves, the results will guide the development of therapeutic targets to improve recovery following nerve injury, slow the progression of neurological diseases, and arrest neural cancers. PUBLIC HEALTH RELEVANCE: Defects in controlling glial cell growth and differentiation cause brain cancers, and inhibit recovery of neural function following neural injuries and demyelinating diseases. A major impediment to developing effective treatment for these debilitating conditions is that mechanisms controlling glial cell development are not well understood. This project will study how the growth of peripheral nerve glial cells, called Schwann cells, is regulated by dominant signaling components concentrated in the extracellular matrix of the developing nerve.