Rodrigues Campos, M; (2014) Bul and Kul are novel components of the Dachsous-Fat planar polarity system. Doctoral thesis , UCL (University College London).

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Abstract

The atypical cadherins Dachsous (Ds) and Fat (Ft) form a system of planar cell polarity that controls the shape of tissues and organs in animals. These cadherins become planar polarised in response to opposing gradients of ds and four jointed (fj) and lead to the downstream polarisation of Dachs, an atypical myosin. Polarisation of Dachs is critical for orientation of cell division and tissue elongation. Even though the proximal-distal gradients are critical, some additional mechanism must exist in order to generate a robust planar polarisation. Via an RNAi screen in the Drosophila wing, we identify two novel components of the Ds-Ft system: Bul and Kul. bul encodes a novel FBXL7 ubiquitin ligase that is recruited to the Ft intracellular domain and promotes degradation of both Ds and its effector protein, Dachs. Loss of Bul results in accumulation of Dachs, similar to loss of Ft. Overexpression of Bul causes downregulation of Dachs, similar to overexpression of Ft intracellular domain. In addition to regulating Dachs, Bul also influences Ds in a similar manner. GFP-tagged Bul localises to the plasma membrane in a Ftdependent manner and is planar polarised. kul encodes an ADAM10 protease that cleaves Ft to promote turnover of Ds-Ft transcellular bridges. Kul cleaves Ft and this cleavage is important for its activity. The action of Kul and Bul contribute in setting up the initial planar polarisation of the Ds-Ft system in response to orienting gradients along the proximal-distal axis of the wing. To achieve planar polarisation, Ft and Bul localise to the proximal side of the cell and thus restrict Ds and Dachs to the distal side of the cell. In this way, epithelial cells can decode vectorial information from a gradient to orient their behaviour.

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