Protocadherin-17 Mediates Collective Axon Extension by Recruiting Actin Regulator Complexes to Interaxonal Contacts

Abstract

In the process of neuronal wiring, axons derived from the same functional group typically extend together, resulting in fascicle formation. How these axons communicate with one another remains largely unknown. Here, we show that protocadherin-17 (Pcdh17) supports this group extension by recruiting actin polymerization regulators to interaxonal contact sites. Pcdh17 is expressed by a subset of amygdala neurons, and it accumulates at axon-axon boundaries because of homophilic binding. Pcdh17 knockout in mice suppressed the extension of these axons. Ectopically expressed Pcdh17 altered the pattern of axon extension. In in-vitro cultures, wild-type growth cones normally migrate along other axons, whereas Pcdh17 null growth cones do not. Pcdh17 recruits the WAVE complex, Lamellipodin, and Ena/VASP to cell-cell contacts, converting these sites into motile structures. We propose that, through these mechanisms, Pcdh17 maintains the migration of growth cones that are in contact with other axons, thereby supporting their collective extension.

Emerging roles of protocadherins: from self-avoidance to enhancement of motility

“…Another report has shown that Pcdh17 knockout in mice results in defects in the extension of axons from specific subdivisions of the amygdala, a center in the brain that regulates emotions and motivation (Hayashi et al, 2014). This phenotype has been confirmed through observations of impaired axon growth from amygdala fragments that had been explanted in vitro, supporting the idea that Pcdh17 mediates axon growth.…”

“…Similar to the classic cadherins, d2-protocadherins accumulate at cell-cell contact sites through homophilic interactions (Hayashi et al, 2014;Hirano et al, 1999;Nakao et al, 2008;Tai et al, 2010). So far, it appears that trans-interactions occur only between the same subtypes (Hoshina et al, 2013;Tai et al, 2010) (S.H., unpublished data).…”

“…For instance, Pcdh17 mutants that lack these cytoplasmic regions induce the lateral clumping of axons when exogenously expressed in neurons of embryonic brains (Hayashi et al, 2014). Similarly, Pcdh19 variants, from which the cytoplasmic region has been deleted, induce the formation of (Yasuda et al, 2007).…”

“…Pcdh10 (also known as OLprotocadherin) and Pcdh17 are detected along axon fibers (Hayashi et al, 2014;Uemura et al, 2007), suggesting that they are involved in axon development or function. It has, indeed, been reported that gene knockout of Pcdh10 in mice causes defects in the formation of various axon tracts, such as the thalamocortical and corticospinal tracts that connect the cerebral cortex and other regions of the central nervous system (Uemura et al, 2007).…”

“…All d2-protocadherins interact with the WAVE complex. Lamellipodin and Ena/VASP associate with the Pcdh17-bound WAVE, and Ena/VASP is assumed to regulate actin polymerization (Hayashi et al, 2014). In the classic-cadherin-based adhesion, a-catenin mediates the linkage of cadherin with actomyosin filaments; without this linkage, cadherins are unable to induce firm cell-cell adhesion (Takeichi, 2014).…”