CYY-1/Cyclin Y and CDK-5 Differentially Regulate Synapse Elimination and Formation for Rewiring Neural Circuits

Abstract

Summary The assembly and maturation of neural circuits require a delicate balance between synapse formation and elimination. The cellular and molecular mechanisms that coordinate synaptogenesis and synapse elimination are poorly understood. In C. elegans, DD motoneurons respecify their synaptic connectivity during development by completely eliminating existing synapses and forming new synapses without changing cell morphology. Using loss- and gain-of-function genetic approaches, we demonstrate that CYY-1, a novel cyclin box-containing protein, drives synapse removal in this process. In addition, cyclin-dependent kinase-5 (CDK-5) facilitates new synapse formation by regulating the transport of synaptic vesicles to the sites of synaptogenesis. Furthermore, we show that coordinated activation of UNC-104/Kinesin3 and Dynein are required for patterning newly formed synapses. During the remodeling process, presynaptic components from eliminated synapses are recycled to new synapses, suggesting that signaling mechanisms and molecular motors link the deconstruction of existing synapses and the assembly of new synapses during structural synaptic plasticity.

Neural circuit rewiring: insights from DD synapse remodeling

“…There is also evidence pointing to the involvement of the cyclin-dependent kinase CDK-5 in modulating UNC-104 activity during remodeling. 23 MT polarity remains plus-end out in all DD neuron processes during remodeling, including those in the dorsal neurites. 22 Thus a combination of UNC-104 and the minus end directed DHC-1/dynein is required to pattern the newly formed synapses along the dorsal DD neurite.…”

“…22 Thus a combination of UNC-104 and the minus end directed DHC-1/dynein is required to pattern the newly formed synapses along the dorsal DD neurite. 23 Concurrent to new synapse formation to dorsal muscles, existing synapses are eliminated from the ventral neurite of DD neurons, and some synaptic vesicle components appear to be recycled during new synapse formation. 23 Emerging evidence implicates both a cyclin Y homolog CYY-1 23 , and the cell death pathway 24 in DD synapse elimination, but the link between the 2 pathways remains to be addressed.…”

Orphan kinases turn eccentric

“…8 These kinases are, however, likely to have additional functions, which remain to be fully characterized. In nematodes PCT-1 and CCNY are required in neurons, 65,69 while in vertebrates CDK16 is essential for spermatogenesis. 9 The precise functions of CCNY-dependent kinases in these processes are, however, still unclear, and it will be important to define the specific substrates of these kinases to understand their mode of action.…”

“…Although PCT-1 and CDK5 have different subcellular localizations, both regulate presynaptic vesicle transport and synapse turnover. 65,69 In contrast to flies and vertebrates, CCNY is not essential in nematodes, probably because WNT signaling in nematodes does not depend on LRP6. 70 In vertebrates, functional analysis of CCNY, PCTAIRE and PFTAIRE genes is more complicated due to the presence of multiple genes.…”

“…Redundancy can also be seen between PCT-1 and CDK5 in the motor neurons of C. elegans. Given the different subcellular localization of these kinases 65 and the different phenotypes of the mutants, 69 it seems likely, however, that these two kinases exert different functions in the same pathway, and it will be important to find out whether PCTAIRE kinases do cooperate with CDK5 in vertebrate neurons as well.…”