Obligatory Activation of SRC and JNK by GDNF for Survival and Axonal Outgrowth of Postnatal Intestinal Neurons

Abstract

The neurotrophin GDNF acts through its co-receptor RET to direct embryonic development of the intestinal nervous system. Since this continues in the post-natal intestine, co-cultures of rat enteric neurons and intestinal smooth muscle cells were used to examine how receptor activation mediates neuronal survival or axonal extension. GDNF-mediated activation of SRC was essential for neuronal survival and axon outgrowth and activated the major downstream signaling pathways. Selective inhibition of individual pathways had little effect on survival but JNK activation was required for axonal maintenance, extension or regeneration. This was localized to axonal endings and retrograde transport was needed for central JUN activation and subsequent axon extension. Collectively, GDNF signaling supports neuronal survival via SRC activation with multiple downstream events, with JNK signaling mediating structural plasticity. These pathways may limit neuron death and drive subsequent regeneration during challenges in vivo such as intestinal inflammation, where supportive strategies could preserve intestinal function.

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Abbreviations

CNS:

Central nervous system

DMEM:

Dulbecco’s minimal essential medium

ENS:

Enteric nervous system

GDNF:

Glial cell line derived neurotrophic factor

ISMC:

Intestinal smooth muscle cell

JNK:

C-Jun N-terminal kinase

LY:

LY294002

PD:

PD98059

RET:

“Re-arranged on transfection”

SB:

SB203580

SP:

SP600125

TNBS:

Trinitrobenzene sulphonic acid

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Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada.

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Correspondence to M. G. Blennerhassett.

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Blennerhassett, M.G., Lourenssen, S.R. Obligatory Activation of SRC and JNK by GDNF for Survival and Axonal Outgrowth of Postnatal Intestinal Neurons. Cell Mol Neurobiol (2021). https://doi.org/10.1007/s10571-021-01048-9

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Keywords

  • Intestine
  • Neuron
  • Retrograde transport
  • Receptor tyrosine kinase
  • Enteric nervous system