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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).
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