Abstract
BackgroundThe 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 FindingsHere, 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/SignificanceOur 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.
Highlights
The mammalian genome contains an expanded repertoire of transmembrane proteins that carry both leucine-rich repeats (LRR) and immunoglobulin (Ig) domains in their extracellular domains [1]
Conclusions/Significance: Our results suggest that 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
We performed experiments that address three basic questions: 1) Can Lrig3 interact with ErbB receptors in vitro? 2) Are ErbB receptors expressed during inner ear development? and 3) Is ErbB signaling necessary for canal morphogenesis? Our results indicate that Lrig3 can interact with ErbB receptors in vitro, reduction of Neuregulin signaling in vivo does not cause any detectable changes in Netrin gene expression or in the structure of the inner ear
Summary
The mammalian genome contains an expanded repertoire of transmembrane proteins that carry both leucine-rich repeats (LRR) and immunoglobulin (Ig) domains in their extracellular domains [1]. Within this LRR-Ig superfamily, only the Lrig subfamily contains both invertebrate and vertebrate orthologs, represented by Dlig ( called Lambik) in flies and Lrig, Lrig, and Lrig in vertebrates. 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. Other receptor tyrosine kinase binding partners have been identified for both Lrig and Lrig, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes
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