Bettina Winckler, Ph.D.
Professor of Neuroscience
Ph.D. 1994, Massachusetts Institute of Technology
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.
L1 substrate promotes axon outgrowth in vivo and in vitro (image by Zofia Lasiecka).