The gene PRICKLE1 is important for human brain function, as mutations in PRCKLE1 are associated with progressive myoclonus epilepsy (PME). Mutations in prickle orthologs could cause seizures in flies, zebrafish and mice, suggesting a conserved role of Prickle protein in seizure from fruit flies to humans. The underlying molecular mechanism how PRICKLE1 mutation causes PME is still unknown.
Prickle1 is part of the planar cell polarity (PCP) pathway, which regulates cell polarity within plane of cell sheets. In Drosophila, prickle is recruited to one side of the cell by another PCP protein, Van Gogh. This asymmetric protein localization of Van Gogh/prickle establishes cell polarity. In zebrafish and Xenopus, loss of Prickle or Van Gogh like (Vangl) genes causes PCP phenotypes, which seemingly supports the Prickle/Vangl protein interaction and the role of Prickle in PCP pathway.
The function of Prickle in mammals has not been analyzed. It is possible that mammalian Prickle also interacts with Vangl to mediate PCP signaling based on the conserved role of prickle from Drosophila to Xenopus. If Prickle1 interacts with Vangl and regulate PCP pathway, the PME we observed in humans might be associated with loss of neuronal polarity and impaired neuron activity. Therefore, to understand whether Prickle1 mediates Vangl signaling in mammals could be a step toward revealing the etiology of PME in human patients.
Therefore, I analyzed the function of Prickle1 in three developmental processes, the limb development, the palate development, and the caudal migration of facial branchimotor neurons (FBMs), in which the function of PCP pathway, especially Vangl2, has been described. Supporting the interaction between Prickle1 and Vangl, mutations in either Prickle1 or Vangl2 leads to shorter limbs. However, Prickle1 and Vangl2 only have limited overlap in mRNA expression in the digit tips. This raises the question as to how impaired Prickle1/Vangl2 protein interaction in these cells in the digit tips cause defective growth of the whole limb. It also suggests alternate function of Prickle1 other than mediating Vangl2 function.
This interaction between Prickle1 and Vangl2 is further challenged by the limited function of Vangl but the essential role of Prickle1 in palate development, which suggests that the function of Prickle1 is independent of Vangl2.
In the caudal migration of FBMs, Prickle1 mutation impairs this migration process dose-dependently. This is different from Vangl2 mutation, which completely blocks the caudal migration and partially impairs the lateral migration of FBMs. More importantly, Prickle1 is expressed by the neurons, while Vangl2 functions in the surrounding cells, which again raises the question as to whether and how the two proteins could interact if they are not expressed in the same cell.
These results together question the model that Prickle1 is the intracellular partner of Vangl2, but support Prickle1 function might be independent of Vangl. Actually, it is possible that Prickle1 is part of gene expression regulation machinery: Prickle1 mutation affects Wnt5a expression in the limb and Shh expression in the palate. Although this regulation mechanism is still unknown, it suggests that defective gene expression might be related to PME caused by PRICKLE1 mutation.