Prickle2, encoded by the planar cell polarity (PCP) genes, is a key component of the noncanonical Wnt/PCP signaling pathway. It plays a crucial role in neural circuit development, which is essential for the proper functioning of the nervous system [1]. Prickle2 is involved in various stages of neural circuit formation, such as the development of the initial segment of neuronal axons, axon elongation and regeneration, dendrite formation, synapse formation, and vesicle transport [1].

In Prickle2 -deficient mice, there are abnormal morphology and motility in the motile cilia of the ependyma and trachea, indicating Prickle2 is required for normal ependymal motile cilia development and function [5]. In neurons, Prickle2 depletion alters cytoskeleton organization, and its levels determine both axon number and axon initial segment (AIS) maturation, with early Prickle2 depletion producing impaired action potential firing [4]. Also, knockdown of Prickle2 affects the subcellular localization of Igsf9b, leading to defects in AnkG and voltage-gated Na+ channel localization, and altered network activity, which may provide insights into the shared pathology of autism spectrum disorder (ASD) and epilepsy [2]. Pathogenic variants in PRICKLE2 in humans cause neurodevelopmental delay, behavioral difficulties, and epilepsy [3].

In conclusion, Prickle2 is essential for neural circuit development, especially in axon and AIS-related processes. Mouse models with Prickle2 deficiency have revealed its role in motile cilia development and function, as well as its implications in neurological disorders like ASD and epilepsy. These findings contribute to understanding the biological functions of Prickle2 and its importance in disease-related research.

References:

1. Yang, Yi, Mao, Yanxia, Zhang, Yao, Xiong, Tao. 2025. Evolving Insights into Prickle2 in Neurodevelopment and Neurological Disorders. In Molecular neurobiology, , . doi:10.1007/s12035-025-04795-8. https://pubmed.ncbi.nlm.nih.gov/40009262/

2. Chowdhury, Md Imrul Hasan, Nishioka, Tomoki, Mishima, Noriko, Kaibuchi, Kozo, Tsuboi, Daisuke. 2020. Prickle2 and Igsf9b Coordinately Regulate the Cytoarchitecture of the Axon Initial Segment. In Cell structure and function, 45, 143-154. doi:10.1247/csf.20028. https://pubmed.ncbi.nlm.nih.gov/32641624/

3. Bayat, Allan, Iqbal, Sumaiya, Borredy, Kim, Rubboli, Guido, Møller, Rikke S. 2021. PRICKLE2 revisited-further evidence implicating PRICKLE2 in neurodevelopmental disorders. In European journal of human genetics : EJHG, 29, 1235-1244. doi:10.1038/s41431-021-00912-y. https://pubmed.ncbi.nlm.nih.gov/34092786/

4. Dorrego-Rivas, Ana, Ezan, Jerome, Moreau, Maïté M, Sans, Nathalie, Montcouquiol, Mireille. 2022. The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling. In Science advances, 8, eabo6333. doi:10.1126/sciadv.abo6333. https://pubmed.ncbi.nlm.nih.gov/36083912/

5. Sowers, Levi P, Yin, Terry, Mahajan, Vinit B, Bassuk, Alexander G. 2014. Defective motile cilia in Prickle2-deficient mice. In Journal of neurogenetics, 28, 146-52. doi:10.3109/01677063.2014.885966. https://pubmed.ncbi.nlm.nih.gov/24708399/