Prickle promotes the formation and maintenance of glutamatergic synapses by stabilizing the intercellular planar cell polarity complex

Abstract

The glutamatergic synapses are assembled and maintained by conserved planar cell polarity proteins.

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

“…Planar Cell Polarity Protein 2 or Prickle 2 (Pk2) is one of these core PCP genes whose mutation has been linked to autism spectrum disorders (ASDs) and epilepsy (26,27). Extensive studies have examined the role of Prickle in epithelial PCP (28)(29)(30), and in neurons, Prickle2 has been implicated in synaptic function (26,27,31,32). However, a clear molecular role for the protein is lacking, both in invertebrates and vertebrates (33,34).…”

Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

“…Again, to avoid complications of PK functions in earlier developmental stages which may be disrupted by straight knockout or conditional knockout from an early embryonic stage, we performed double conditional knockout of PK1 and PK2 using CRISPR in hippocampus or medial prefrontal cortex at postnatal day 7 and quantified synapse numbers at postnatal day 21 and found synapse numbers were reduced by 70%‐80%. Using floxed alleles of PK1 or PK2, we also observed around 30%‐40% reduction of synapse numbers in single PK1 or PK2 cKO 10 . A number of possibilities may explain the remaining 20%‐30% glutamatergic synapses in the double cKO: (a) some synapses maybe be assembled by the other less abundant PK, PK3; (b) formation of glutamatergic synapses starts before postnatal day 7 and some synapses may have already been formed before we performed viral injections at day 7; (c) the efficiency of knockout using either CRISPR or floxed alleles may not be 100%; (d) Existing PK protein may still persist in neurons and synapses after even a complete knockout; (e) a distinct signaling pathway, separate from PCP, may assemble the remaining synapses.…”

“…Vangl2 promotes the interaction between Celsr3 and PK2, whereas PK2 inhibits the interaction between Celsr3 and Vangl2 (Figure 3). This Vangl2‐PK2 interaction may result in an accumulation of the PK2 protein in the PSD to stabilize synapses and have an opposite effect on synapse stability of the other Vangl2 function: reducing the Celsr3/Frizzled3‐Celsr3 intercellular complex 10 . The co‐culture results also suggest that the asymmetric intercellular complex may specify the directionality of presynaptic and postsynaptic compartments and thus determines the direction of synaptic transmission (Figure 4).…”

“…B, PCP components form asymmetric complexes at glutamatergic synapses similar to the cell‐cell junctions during PCP signaling at epithelial adherens junctions. PCP proteins interact with a number of core synaptic proteins, such as Bassoon, PSD95, SV2 and synaptophysin 8‐10 …”

Epilepsy gene prickle ensures neuropil glial ensheathment through regulating cell adhesion molecules

“… 11 , 12 In mice, fly and zebrafish, Prickle has also been found to be expressed in the nervous system, 1 , 3 , 13 and it participates in various neural developmental processes, including neurite growth, neural migration, and synapse formation and maintenance. 14 , 15 , 16 , 17 Notably, Prickle1 was also detected in two types of glia, namely microglia and oligodendrocyte 18 ; however, little is known about its function in glial cells.…”