During development, dorsal root ganglia (DRG) sensory neurons rely on target-derived neurotrophins for survival. Previous research has demonstrated that location of neurotrophin stimulation can specify distinct neuronal responses. Here, we further elucidate the role of retrograde neurotrophin transport in mediating distinct cellular responses. We find that the transcription factor MEF2D is specifically induced in sensory neurons by distal axon neurotrophin stimulation. Additionally, MEF2D regulates the expression of bcl-w , an anti-apoptotic Bcl-2 family member. Expression of mef2d and bcl-w requires activation of a spatially selective Erk5/MEF2D pathway. Thus, retrograde neurotrophin signaling can preferentially activate a distinct transcriptional program to promote survival of neurons that have innervated target tissues.
The identification of bcl-w as a retrograde response gene suggests that it plays a role in survival of DRG neurons. We show that bcl-w -/- mice develop adult-onset progressive decline in detection of noxious thermal stimuli and reduced nociceptor epidermal innervation in the hindpaws. There is no cell loss in DRGs of symptomatic bcl-w -/- mice, suggesting a primary pathology of axonal degeneration. Consistent with a role for Bcl-w in axonal maintenance, we find that Bcl-w is highly expressed in sensory neuron axons. We also find that mitochondria from bcl-w -/- DRGs exhibit abnormal morphology and function. Interestingly, the sensory neuron dysfunction in bcl-w -/- mice resembles progressive small fiber sensory neuropathy.
An additional mouse model that highlights the importance of retrograde axonal transport is the Cramping 1 (Cra1) mouse line. Cra1/+ mice were originally reported to demonstrate late-onset motor neuron degeneration due to dysfunction of the retrograde motor protein dynein. Surprisingly, we find that Cra1/+ mice show an early-onset, stable phenotype of hindlimb cramping and reduced grip strength without motor neuron loss. Recent research on Cra1/+ mice has suggested the primary pathology is loss of proprioceptive neurons; thus, we propose that alterations in dynein in Cra1/+ mice leads to early onset sensory neuron dysfunction, highlighting the in vivo importance of retrograde axonal transport in sensory neuron survival.
The studies presented here extend our understanding of the spatial aspects of neurotrophin signaling, and demonstrate the importance of retrograde axonal transport in sensory neurons.
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 71/02, Dissertation Abstracts International|
|Keywords:||Axonal degeneration, Neuronal survival, Neurotrophin transport, Sensory neurons|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be