Prickle (protein)

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. 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. Prickle interacts with flamingo to regulate sensory axon advance at the transition between the peripheral nervous system and the central nervous system. Also, Prickle1 interacts with RE1-silencing transcription factor (REST) by transporting REST out of the nucleus. REST turns off several critical genes in neurons by binding to particular regions of DNA in the nucleus.

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

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

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

References

References

1. (December 2003). "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor". Molecular and Cellular Biology.
2. (November 2008). "A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome". American Journal of Human Genetics.
3. (April 2003). "Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements". Current Biology.
4. (April 2012). "Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis". Developmental Biology.
5. (June 2013). "Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis". Human Molecular Genetics.
6. (February 2003). "Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle". International Journal of Molecular Medicine.
7. (February 2006). "Expression of planar cell polarity genes during development of the mouse CNS". The European Journal of Neuroscience.
8. (October 2011). "The core planar cell polarity gene prickle interacts with flamingo to promote sensory axon advance in the Drosophila embryo". Developmental Biology.
9. (July 2003). "Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning". Development.
10. (July 2005). "Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding". Nature Cell Biology.
11. (September 1999). "The balance between isoforms of the prickle LIM domain protein is critical for planar polarity in Drosophila imaginal discs". Genes & Development.
12. "Evaluating PRICKLE mutations in human epilepsy and animal models". The University of Iowa.