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Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation
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, Argentina.
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, Argentina.
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, Argentina.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0001-6891-6996
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2021 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 148, no 16, article id dev197020Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
The Dompany of Biologists , 2021. Vol. 148, no 16, article id dev197020
Keywords [en]
Cutaneous sensory innervation and nociceptive neurons, Dorsal root ganglia (DRG), GDNF, GFRα, Lrig family members, Mouse, Ret
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-187480DOI: 10.1242/dev.197020ISI: 000691627500007PubMedID: 34338291Scopus ID: 2-s2.0-85114200159OAI: oai:DiVA.org:umu-187480DiVA, id: diva2:1593638
Available from: 2021-09-13 Created: 2021-09-13 Last updated: 2022-09-09Bibliographically approved

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