Abstract
Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The ‘core’ PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pkpk but not pksple and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.
Highlights
Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from Drosophila to humans, through input into cellular orientation across tissues, individual cell fate decisions, and the coordinated movement of groups of cells [1,2,3,4,5,6,7,8]
Our functional studies established a role for Nmo kinase during PCP establishment in addition to its known role during the subsequent rotation process
The phosphorylation of the Pk isoform serves as a way to limit the activity of the minor isoform in tissues where Pk-Sple is the major functional isoform
Summary
Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from Drosophila to humans, through input into cellular orientation across tissues, individual cell fate decisions, and the coordinated movement of groups of cells [1,2,3,4,5,6,7,8]. The two core Fz/PCP pathway complexes comprise of Frizzled/Dishevelled/Diego (Fz/Dsh/Dgo) in one complex, and Van Gogh/Prickle (Vang/Pk) (Vang, known as Strabismus/Stbm) in the other. These complexes are localized to opposite sides of the cell and stabilized intercellularly via the atypical cadherin Flamingo (Fmi) associating with both complexes [1,2,3,4,5,6,7]. Recent work has shown that this isoform balance is regulated transcriptionally at the tissue level in the wing, where Pk mRNA is present at 1015-fold higher levels than Pk-Sple mRNA [17]. It is unclear how the balance is maintained in the eye, because it cannot be explained by transcriptional regulation: Pk mRNA is expressed at slightly higher levels than Pk-Sple mRNA [17], even though Pk-Sple is
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