University of Virginia Health System

Email Address: bwinckler@virginia.edu

Neurons extend two distinct types of processes , axons and dendrites , in order to connect to distant targets and establish functional circuits. The growth of axons and dendrites is regulated by a multitude of proteins , among them cell adhesion molecules , which promote and guide growth. The L1 cell adhesion molecule is found on axons and is needed for proper formation of several major axon tracts during development. In fact , mutations in the L1 gene cause a severe human neurodevelopmental defect called MASA/CRASH syndrome. After development is complete , new axon growth can sometimes occur during regenerative processes after injury. Intriguingly , L1 has been implicated in regeneration of axons after spinal injury. Additionally , L1 levels are upregulated in post-stroke cortex and L1 might serve important functions during post-stroke axonal sprouting to re-establish functional circuits.

Axon growth mediated by L1 requires that L1 molecules at the tip of the growing axon are internalized by a process called endocytosis and subsequently recycled back to the cell surface. Our lab has uncovered an additional crucial role for endocytosis in L1 function: it is required to target L1 properly to the growing axon. L1 function and endocytosis are therefore intricately connected. Endocytosis and the subsequent traffic control in endosomes are complex , especially in a cell as large and spatially diversified as a mammalian neuron. Understanding neuronal endosomes is crucial given the large number of neuronal processes in which endocytosis plays a role: retrograde neurotrophic signaling , turnover and degradation of proteins , axonal pathfinding during development , synaptic vesicle recycling , synaptic plasticity , neuropathic pain , addiction , and more.

Work in our laboratory therefore focuses on understanding the functional links between endosomal regulators , trafficking of adhesion molecules , and axon outgrowth in health and disease.

Molecular Cell and Developmental Biology

Neurons display a complex architecture that underlies their ability to integrate signals and transmit them over long distances. In particular , neurons elaborate morphologically and functionally distinct domains , such as axons , dendrites , synapses , Nodes of Ranvier , and axonal initial segments in order to carry out their signaling functions. Different functional domains differ in the membrane proteins that are displayed on their surfaces. This segregation of membrane proteins to different domains enables the neuron to grow out axons and dendrites using specific cell adhesion molecules (such as L1) , and to ultimately elaborate synapses and signal vectorially. Proper functioning of neurons , therefore , depends on correctly targeting a large number of proteins to specific cellular sites of action. Incorrect protein targeting has been linked to a variety of disease states and abnormalities , including neurological disorders. My lab studies how vertebrate neurons assemble and maintain the distinct plasma membrane domains that underlie neuronal function with a particular focus on axons and axon initial segments.  Our long-term goal is to understand the elaboration of neuronal architecture on a molecular level and its disturbance in disease states. Currently , we are characterizing the cellular mechanisms and molecular regulation of polarized membrane transport in neurons , focusing on the L1 CAM family of adhesion receptors.