Functional Regeneration of Brachial Sensory Afferents to the Brainstem.
Wong, Laura.
2014
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Abstract: Spinal cord
injury leads to devastating paralysis and paresis, in large part because damaged axons
in the central nervous system fail to regenerate. Recovery following a spinal cord
injury will require axons to restore synaptic connectivity with denervated targets
several centimeters from the site of injury. This will require therapeutic agents that
promote regeneration across long ... read moredistances. Here, we report that brief systemic artemin
treatment promotes regeneration of sensory axons to the brainstem following brachial
dorsal root crush in an adult rat. Axon regeneration to the brainstem takes more than
three months, consistent with slow growth across the three to four centimeter distance
to reach the brainstem. Artemin not only stimulates robust regeneration of large,
myelinated sensory axons to the brainstem, but it also promotes functional reinnervation
of the appropriate target region, the cuneate nucleus. Remarkably, axons regenerate
appropriately in the dorsal columns and establish connections with the correct nucleus
in the brainstem without the addition of exogenous guidance molecules. Artemin signals
primarily through the RET tyrosine kinase, an interaction that requires the
non-signaling co-receptor GFRα3. Previous studies report limited GFRα3
expression on large sensory neurons, suggesting that artemin could not signal in these
neurons. Our findings, however, demonstrate that artemin promotes robust regeneration of
large, myelinated sensory afferents suggesting some manner by which artemin signals in
these neurons. Using a cell sorting technique, we demonstrated that the expression of
GFRα3 is similar in myelinated and unmyelinated adult sensory neurons. This
suggests that artemin likely induces long-distance regeneration by binding GFRα3
and RET. Although artemin is delivered for just two-weeks, regeneration to the brainstem
requires more than three months, suggesting that brief trophic support may initiate
intrinsic growth programs that remain active until targets are reached. Artemin may
therefore represent a promising therapy for targeted sensory axon regeneration and
functional reinnervation after spinal cord injury. In addition, understanding the
mechanism by which artemin promotes regeneration may provide important insights into the
development of future therapeutics to promote recovery following spinal cord
injury.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Neuroscience.
Advisor: Eric Frank.
Committee: James Schwob, Kathleen Dunlab, Daniel Jay, and Zhigang He.
Keywords: Neurosciences, and Physiology.read less - ID:
- d504rx66s
- Component ID:
- tufts:20639
- To Cite:
- TARC Citation Guide EndNote
