Gastrointestinal Diseases Research Unit and Queen's University, Kingston, ON, K7L 2V7, Canada.
Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L2V7, Canada.
Cell Mol Neurobiol. 2022 Jul;42(5):1569-1583. doi: 10.1007/s10571-021-01048-9. Epub 2021 Feb 5.
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.
神经胶质细胞源性神经营养因子（GDNF）通过其共受体 RET 发挥作用，指导肠道神经系统的胚胎发育。由于这种作用在出生后肠道中仍在继续，因此使用大鼠肠神经元和平滑肌细胞的共培养物来研究受体激活如何介导神经元存活或轴突延伸。SRC 的 GDNF 介导激活对于神经元存活和轴突生长至关重要，并激活了主要的下游信号通路。选择性抑制单个通路对存活几乎没有影响，但 JNK 激活对于轴突维持、延伸或再生是必需的。这种激活定位于轴突末端，并且需要逆行运输来激活中央 JUN 和随后的轴突延伸。总的来说，GDNF 信号通过 SRC 激活支持神经元存活，具有多种下游事件，其中 JNK 信号介导结构可塑性。这些途径可能会限制神经元死亡，并在体内挑战（如肠道炎症）期间驱动随后的再生，在这种情况下，支持性策略可以保留肠道功能。
