Prickle (protein)

Prickle is also known as REST/NRSF-interacting LIM domain protein, which is a putative nuclear translocation receptor.[1] Prickle is part of the non-canonical Wnt signaling pathway that establishes planar cell polarity.[2] A gain or loss of function of Prickle1 causes defects in the convergent extension movements of gastrulation.[3] In epithelial cells, Prickle2 establishes and maintains cell apical/basal polarity.[4] Prickle1 plays an important role in the development of the nervous system by regulating the movement of nerve cells.[5]

The first prickle protein was identified in Drosophila as a planar cell polarity protein. Vertebrate prickle-1 was first found as a rat protein that binds to a transcription factor, neuron-restrictive silencer factor (NRSF). It was then recognized that other vertebrates including mice and humans have two genes that are related to Drosophila prickle.[6] Mouse prickle-2 was found to be expressed in mature neurons of the brain along with mouse homologs of Drosophila planar polarity genes flamingo and dischevelled.[7] Prickle interacts with flamingo to regulate sensory axon advance at the transition between the peripheral nervous system and the central nervous system.[8] Also, Prickle1 interacts with RE1-silencing transcription factor (REST) by transporting REST out of the nucleus.[1] REST turns off several critical genes in neurons by binding to particular regions of DNA in the nucleus.[1]

Prickle is recruited to the cell surface membrane by strabismus, another planar cell polarity protein.[9] In the developing Drosophila wing, prickle becomes concentrated at the proximal side of cells.[9] Prickle can compete with the ankyrin-repeat protein Diego for a binding site on Dishevelled.[10]

In Drosophila, prickle is present inside cells in multiple forms due to alternative splicing of the prickle mRNA.[11] The relative levels of the alternate forms may be regulated and involved in the normal control of planar cell polarity.[11]

Mutations in Prickle genes can cause epilepsy in humans by perturbing Prickle function.[12] One mutation in Prickle1 gene can result in Prickle1-Related Progressive Myoclonus Epilepsy-Ataxia Syndrome.[2] This mutation disrupts the interaction between prickle-like 1 and REST, which results in the inability to suppress REST.[2] Gene knockdown of Prickle1 by shRNA or dominant-negative constructs results in decreased axonal and dendritic extension in neurons in the hippocampus.[5] Prickle1 gene knockdown in neonatal retina causes defects in axon terminals of photoreceptors and in inner and outer segments.[5]