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The Core PCP Protein Prickle2 Regulates Axon Number and AIS Maturation by Binding to AnkG and Modulating Microtubule Bundling

Abstract

Core planar cell polarity (PCP) genes, which are involved in various neurodevelopmental disorders such as neural tube closure, epilepsy, and autism spectrum disorder, have poorly defined molecular signatures in neurons, mostly synapse-centric. Here, we show that the core PCP protein Prickle-like protein 2 (Prickle2) controls neuronal polarity and is a previously unidentified member of the axonal initial segment (AIS) proteome. We found that Prickle2 is present and colocalizes with AnkG480, the AIS master organizer, in the earliest stages of axonal specification and AIS formation. Furthermore, by binding to and regulating AnkG480, Prickle2 modulates its ability to bundle microtubules, a crucial mechanism for establishing neuronal polarity and AIS formation. Prickle2 depletion alters cytoskeleton organization, and Prickle2 levels determine both axon number and AIS maturation. Last, early Prickle2 depletion produces impaired action potential firing.

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References
1.
Baas P, Black M, Banker G . Changes in microtubule polarity orientation during the development of hippocampal neurons in culture. J Cell Biol. 1989; 109(6 Pt 1):3085-94. PMC: 2115969. DOI: 10.1083/jcb.109.6.3085. View

2.
Ehaideb S, Iyengar A, Ueda A, Iacobucci G, Cranston C, Bassuk A . prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies. Proc Natl Acad Sci U S A. 2014; 111(30):11187-92. PMC: 4121842. DOI: 10.1073/pnas.1403357111. View

3.
Guo W, Dittlau K, Van Den Bosch L . Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications. Semin Cell Dev Biol. 2019; 99:133-150. DOI: 10.1016/j.semcdb.2019.07.010. View

4.
Unsain N, Bordenave M, Martinez G, Jalil S, von Bilderling C, Barabas F . Remodeling of the Actin/Spectrin Membrane-associated Periodic Skeleton, Growth Cone Collapse and F-Actin Decrease during Axonal Degeneration. Sci Rep. 2018; 8(1):3007. PMC: 5812996. DOI: 10.1038/s41598-018-21232-0. View

5.
Hale R, Strutt D . Conservation of Planar Polarity Pathway Function Across the Animal Kingdom. Annu Rev Genet. 2015; 49:529-51. DOI: 10.1146/annurev-genet-112414-055224. View