Fig. 7. Proposed model for the Lrig3/Ntn1 feedback loop. (A) A diagrammatic view of the lateral pouch during canal morphogenesis. Cross-repressive interactions between Lrig3 and Ntn1 define the boundary between fusing (blue) and non-fusing (red) regions of the otic epithelium. When the regulatory loop is interrupted by loss of Lrig3, fusion is expanded, whereas in Ntn1 mutants, fusion does not occur. Interactions between Lrig3 and Ntn1 ensure that these two genes become confined to distinct domains of the lateral pouch. (B) We propose the following model for the Lrig3/Ntn1 feedback loop. Lrig3 is present throughout the canal pouch before fusion and inhibits activity of a receptor tyrosine kinase (RTK) signaling pathway (1). Subsequently, fusion is initiated by an unknown fusion plate signal, which we hypothesize acts through the RTK pathway by inhibiting Lrig3 (2), resulting in transcription of Ntn1 (3). Lrig3 initially continues to be transcribed, as expected for a feedback-induced antagonist. However, the increased levels of Ntn1 eventually inhibit Lrig3 expression, either by inhibiting Lrig3 or by potentiating activity of the fusion plate signal. For example, Ntn1 protein may augment activity of the RTK pathway by promoting basal lamina breakdown (4).