Prickle/spiny-legs isoforms control the polarity of the apical microtubule network in planar cell polarity

Abstract

Microtubules (MTs) are substrates upon which plus-and minus-end directed motors control the directional movement of cargos that are essential for generating cell polarity. Although centrosomal MTs are organized with plus-ends away from the MT organizing center, the regulation of non-centrosomal MT polarity is poorly understood. Increasing evidence supports the model that directional information for planar polarization is derived from the alignment of a parallel apical network of MTs and the directional MT-dependent trafficking of downstream signaling components. The Fat/Dachsous/Fourjointed (Ft/Ds/Fj) signaling system contributes to orienting those MTs. In addition to previously defined functions in promoting asymmetric subcellular localization of 'core' planar cell polarity (PCP) proteins, we find that alternative Prickle (Pk-Sple) protein isoforms control the polarity of this MT network. This function allows the isoforms of Pk-Sple to differentially determine the direction in which asymmetry is established and therefore, ultimately, the direction of tissue polarity. Oppositely oriented signals that are encoded by oppositely oriented Fj and Ds gradients produce the same polarity outcome in different tissues or compartments, and the tissue-specific activity of alternative Pk-Sple protein isoforms has been observed to rectify the interpretation of opposite upstream directional signals. The control of MT polarity, and thus the directionality of apical vesicle traffic, by Pk-Sple provides a mechanism for this rectification.

Planar cell polarity in development and disease

“…As it turns out, these polarized microtubule arrays can bias the transport of core PCP particles consisting of Dsh, Fz and Fmi towards one side of the cell, aiding the PCP patterning process 36–39 . These Fmi–Fz–Dsh accumulations are preferentially trafficked towards the plus ends of microtubules, showing a bias in directionality similar to plus-end tip tracking proteins such as EB1 38 (Fig. 2).…”

“…It has separately been shown that intact PCP patterns are necessary for the polarization of microtubule arrays 24,38,41 , demonstrating that intricate and mutual relationships exist between microtubule polarity and planar polarity patterning.…”

“…Microtubule plus ends are often oriented towards Ds in cells predominately expressing Pk and towards Ft in cells predominantly expressing Sple 38 . Using Ft–Ds–Fj polarity cues to orient microtubules results in a bias in the directional transport of core PCP signalling components 36,38 , thereby providing a means of coupling these two signalling pathways 39,58 . However, detailed molecular mechanism through which these microtubules are oriented in response to the Ft–Ds gradient and whether this mode of orienting PCP is conserved in tissues other than the fly wing, as well as in other species, remains unclear.…”

“…Localization of PCP components with respect to Ft–Ds axis depends on the levels of expression of two Prickle isoforms: Prickle (Pk) and Spiny Legs (Sple) 38 . In cells expressing predominantly Pk, Vang–Pk localizes on the same side of the cell as Ft, but in cells expressing mostly Sple, Vang–Sple localizes together with Ds.…”

Planar Polarity: Converting a Morphogen Gradient into Cellular Polarity

“…For example, Ds–Ft activity orients microtubules and thus participates in Fz and Dsh trafficking to the distal side of a cell to reinforce initial polarity [17,18]. Also, Pk isoforms have recently been shown to couple Ds–Ft to the core system at late stages of PCP reinforcement by ‘interpreting’ the Ds–Ft gradient to orient microtubules [19,20]. The new work from Hale et al .…”