Abstract
Lrig proteins are conserved transmembrane proteins that modulate a variety of signaling pathways from worm to humans. In mammals, there are three family members – Lrig1, Lrig2, and Lrig3 – that are defined by closely related extracellular domains with a similar arrangement of leucine rich repeats and immunoglobulin domains. However, the intracellular domains show little homology. Lrig1 inhibits EGF signaling through internalization and degradation of ErbB receptors. Although Lrig3 can also bind ErbB receptors in vitro, it is unclear whether Lrig2 and Lrig3 exhibit similar functions to Lrig1. To gain insights into Lrig gene functions in vivo, we compared the expression and function of the Lrigs in the inner ear, which offers a sensitive system for detecting effects on morphogenesis and function. We find that all three family members are expressed in the inner ear throughout development, with Lrig1 and Lrig3 restricted to subsets of cells and Lrig2 expressed more broadly. Lrig1 and Lrig3 overlap prominently in the developing vestibular apparatus and simultaneous removal of both genes disrupts inner ear morphogenesis. This suggests that these two family members act redundantly in the otic epithelium. In contrast, although Lrig1 and Lrig2 are frequently co-expressed, Lrig1−/−;Lrig2−/− double mutant ears show no enhanced structural abnormalities. At later stages, Lrig1 expression is sustained in non-sensory tissues, whereas Lrig2 levels are enhanced in neurons and sensory epithelia. Consistent with these distinct expression patterns, Lrig1 and Lrig2 mutant mice exhibit different forms of impaired auditory responsiveness. Notably, Lrig1−/−;Lrig2−/− double mutant mice display vestibular deficits and suffer from a more severe auditory defect that is accompanied by a cochlear innervation phenotype not present in single mutants. Thus, Lrig genes appear to act both redundantly and independently, with Lrig2 emerging as the most functionally distinct family member.
Highlights
Protein-protein interactions are critical for diverse and complex biological functions throughout the animal kingdom, including nervous system development, cell adhesion and signaling, tissue morphogenesis, the immune response and human disease [1,2,3,4]
To begin to determine whether these three family members play overlapping functions, we compared their expression patterns in the inner ear, either by in situ hybridization (Lrig1) or by examining the expression of bgeo reporter genes inserted into the Lrig2 (Figure S1) and Lrig3 [28] loci
By analyzing multiple aspects of inner ear development and function, we found that Lrig1 and Lrig3 cooperate to control inner ear morphogenesis, whereas Lrig1 and Lrig2 appear to affect largely distinct aspects of inner ear function
Summary
Protein-protein interactions are critical for diverse and complex biological functions throughout the animal kingdom, including nervous system development, cell adhesion and signaling, tissue morphogenesis, the immune response and human disease [1,2,3,4]. The large immunoglobulin (Ig) superfamily of cell adhesion molecules is defined by the presence of Ig domains, which can mediate highly specific homophilic and heterophilic binding [7,8] Despite their abundance, LRR and Ig motifs are rarely found in the same protein, with only several dozen mammalian genes encoding LRR-Ig proteins that fall into twelve gene families [3,9,10]. LRR and Ig motifs are rarely found in the same protein, with only several dozen mammalian genes encoding LRR-Ig proteins that fall into twelve gene families [3,9,10] Most of these proteins are vertebrate-specific and show discrete expression in the developing nervous system, suggesting that expansion of the LRRIg family may have contributed to the increased complexity of the vertebrate nervous system. The invertebrate-specific Kekkon proteins, on the other hand, modulate signaling by binding to and downregulating EGF receptors [11,12]
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