Vertebrate Lrig3-ErbB Interactions Occur In Vitro but Are Unlikely to Play a Role in Lrig3-Dependent Inner Ear Morphogenesis
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AbstractBackground: The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes.
Methodology/Principal Findings: Here, we report that Lrig3, like Lrig1, is able to interact with ErbB receptors in vitro. We examined the in vivo significance of these interactions in the inner ear, where Lrig3 controls semicircular canal formation by determining the timing and extent of Netrin1 expression in the otic vesicle epithelium. We find that ErbB2 and ErbB3 are present in the early otic epithelium, and that Lrig3 acts cell-autonomously here, as would be predicted if Lrig3 regulates ErbB2/B3 activity. However, inhibition of ErbB activation in the chick otic vesicle has no detectable effect on Netrin gene expression or canal morphogenesis.
Conclusions/Significance: Our results suggest that although both Lrig1 and Lrig3 can interact with ErbB receptors in vitro, modulation of Neuregulin signaling is unlikely to contribute to Lrig3-dependent processes of inner ear morphogenesis. These results highlight the similar binding properties of Lrig1 and Lrig3 and underscore the need to determine how these two family members bind to and regulate different receptors to affect diverse aspects of cell behavior in vivo.
CitationPLoS One. 2010 Feb 1; 5(2):e8981
- In vivo analysis of Lrig genes reveals redundant and independent functions in the inner ear.
- Authors: Del Rio T, Nishitani AM, Yu WM, Goodrich LV
- Issue date: 2013
- Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3).
- Authors: Rafidi H, Mercado F 3rd, Astudillo M, Fry WH, Saldana M, Carraway KL 3rd, Sweeney C
- Issue date: 2013 Jul 26
- Cross-repressive interactions between Lrig3 and netrin 1 shape the architecture of the inner ear.
- Authors: Abraira VE, Del Rio T, Tucker AF, Slonimsky J, Keirnes HL, Goodrich LV
- Issue date: 2008 Dec
- Analysis of Netrin 1 receptors during inner ear development.
- Authors: Matilainen T, Haugas M, Kreidberg JA, Salminen M
- Issue date: 2007
- Eya1 regulates the growth of otic epithelium and interacts with Pax2 during the development of all sensory areas in the inner ear.
- Authors: Zou D, Silvius D, Rodrigo-Blomqvist S, Enerbäck S, Xu PX
- Issue date: 2006 Oct 15
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