The role of Netrin-1 in semicircular canal morphogenesis

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The role of Netrin-1 in semicircular canal morphogenesis

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Title: The role of Netrin-1 in semicircular canal morphogenesis
Author: Nishitani, Allison
Citation: Nishitani, Allison. 2014. The role of Netrin-1 in semicircular canal morphogenesis. Doctoral dissertation, Harvard University.
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Abstract: The vestibular system of the inner ear detects head position using three orthogonally oriented semicircular canals. Vestibular function relies on precise canal shape and orientation, and slight changes can cause vestibular defects. Canals are sculpted from pouches that protrude from the otic vesicle, the simple sphere of epithelium that forms the inner ear. In the center of each pouch, a "fusion plate" forms where cells lose their epithelial morphology and the basement membrane breaks down. The opposing layers of the fusion plate intercalate and are subsequently removed, creating a canal. Proper fusion depends on Netrin-1, which regulates basement membrane breakdown during fusion in mice, although the underlying molecular mechanism is unknown. This dissertation describes our work to better understand the cellular effects of Netrin-1 during canal formation. Although vestibular apparatus structure is shared among species, some developmental events that lead to this structure differ. For example, while fusion plate basement membrane breakdown is conserved, apoptosis is required for fusion in chicks, but not in mice. We used gain-of-function approaches to determine the main cellular effect of Netrin-1 during fusion in chicks and mice. We show that overexpression of Netrin-1 in chicks prevents canal fusion from occurring normally by interfering with apoptosis. On the other hand, we show that ectopic expression of Netrin-1 in mice using a conditional expression allele causes excessive fusion, resulting in canal truncation. This suggests that Netrin-1 may play divergent roles during canal morphogenesis in chicks and mice. To determine if Netrin-1 regulates the basement membrane in other contexts, we created a Netrin-1 conditional null allele. This was necessary because existing Netrin-1 mutants express residual Netrin-1 protein, which could be sufficient to rescue basement membrane defects in other tissues, and because existing mutants die shortly after birth, preventing postnatal analysis. Complete loss of Netrin-1 protein in our newly generated mice does not cause more severe defects in fusion compared to existing Netrin-1 hypomorphs, suggesting that residual Netrin-1 protein does not affect the basement membrane during fusion in Netrin-1 hypomorphs. Future work will determine if complete loss of Netrin-1 affects basement membrane integrity in other tissues.
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