Laboratorio de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, CP1121, Argentina.
Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, Umeå, 901 87, Sweden.
Development. 2021 Aug 15;148(16). doi: 10.1242/dev.197020. Epub 2021 Aug 12.
Negative feedback loops represent a regulatory mechanism that guarantees that signaling thresholds are compatible with a physiological response. Previously, we established that Lrig1 acts through this mechanism to inhibit Ret activity. However, it is unclear whether other Lrig family members play similar roles. Here, we show that Lrig1 and Lrig3 are co-expressed in Ret-positive mouse dorsal root ganglion (DRG) neurons. Lrig3, like Lrig1, interacts with Ret and inhibits GDNF/Ret signaling. Treatment of DRG neurons with GDNF ligands induces a significant increase in the expression of Lrig1 and Lrig3. Our findings show that, whereas a single deletion of either Lrig1 or Lrig3 fails to promote Ret-mediated axonal growth, haploinsufficiency of Lrig1 in Lrig3 mutants significantly potentiates Ret signaling and axonal growth of DRG neurons in response to GDNF ligands. We observe that Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold, which correlates with a significant increase in the expression of the cold-responsive channel TrpA1. Together, our findings provide insights into the in vivo functions through which Lrig genes control morphology, connectivity and function in sensory neurons.
负反馈回路代表一种调节机制，可确保信号阈值与生理反应兼容。此前，我们已经证实 Lrig1 通过该机制抑制 Ret 活性。然而，其他 Lrig 家族成员是否发挥类似作用尚不清楚。在这里，我们发现 Lrig1 和 Lrig3 在 Ret 阳性的小鼠背根神经节 (DRG) 神经元中共表达。与 Lrig1 一样，Lrig3 与 Ret 相互作用并抑制 GDNF/Ret 信号。用 GDNF 配体处理 DRG 神经元会显著增加 Lrig1 和 Lrig3 的表达。我们的研究结果表明，尽管单独缺失 Lrig1 或 Lrig3 都不能促进 Ret 介导的轴突生长，但 Lrig1 在 Lrig3 突变体中的单倍不足会显著增强 Ret 信号，并增强 DRG 神经元对 GDNF 配体的轴突生长反应。我们观察到 Lrig1 和 Lrig3 冗余地发挥作用，以确保非肽能轴突的皮肤神经支配和对冷的行为敏感性，这与冷响应通道 TrpA1 的表达显著增加相关。总之，我们的研究结果提供了关于 Lrig 基因在感觉神经元中控制形态、连接和功能的体内功能的深入了解。
