Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation.

Autor:	De Vincenti AP; 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., Alsina FC; 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., Ferrero Restelli F; 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., Hedman H; Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, Umeå, 901 87, Sweden., Ledda F; 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.; Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, C1405, Argentina., Paratcha G; 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.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2021 Aug 15; Vol. 148 (16). Date of Electronic Publication: 2021 Aug 12.
DOI:	10.1242/dev.197020
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2021. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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