The Interaction of TRAF6 With Neuroplastin Promotes Spinogenesis During Early Neuronal Development

TY - JOUR

T1 - The Interaction of TRAF6 With Neuroplastin Promotes Spinogenesis During Early Neuronal Development

AU - Vemula, Sampath Kumar

AU - Malci, Ayse

AU - Junge, Lennart

AU - Lehmann, Anne-Christin

AU - Rama, Ramya

AU - Hradsky, Johannes

AU - Matute, Ricardo A

AU - Weber, André

AU - Prigge, Matthias

AU - Naumann, Michael

AU - Kreutz, Michael R

AU - Seidenbecher, Constanze I

AU - Gundelfinger, Eckart D

AU - Herrera-Molina, Rodrigo

N1 - Copyright © 2020 Vemula, Malci, Junge, Lehmann, Rama, Hradsky, Matute, Weber, Prigge, Naumann, Kreutz, Seidenbecher, Gundelfinger and Herrera-Molina.

PY - 2020/12/9

Y1 - 2020/12/9

N2 - Correct brain wiring depends on reliable synapse formation. Nevertheless, signaling codes promoting synaptogenesis are not fully understood. Here, we report a spinogenic mechanism that operates during neuronal development and is based on the interaction of tumor necrosis factor receptor-associated factor 6 (TRAF6) with the synaptic cell adhesion molecule neuroplastin. The interaction between these proteins was predicted in silico and verified by co-immunoprecipitation in extracts from rat brain and co-transfected HEK cells. Binding assays show physical interaction between neuroplastin's C-terminus and the TRAF-C domain of TRAF6 with a Kd value of 88 μM. As the two proteins co-localize in primordial dendritic protrusions, we used young cultures of rat and mouse as well as neuroplastin-deficient mouse neurons and showed with mutagenesis, knock-down, and pharmacological blockade that TRAF6 is required by neuroplastin to promote early spinogenesis during in vitro days 6-9, but not later. Time-framed TRAF6 blockade during days 6-9 reduced mEPSC amplitude, number of postsynaptic sites, synapse density and neuronal activity as neurons mature. Our data unravel a new molecular liaison that may emerge during a specific window of the neuronal development to determine excitatory synapse density in the rodent brain.

AB - Correct brain wiring depends on reliable synapse formation. Nevertheless, signaling codes promoting synaptogenesis are not fully understood. Here, we report a spinogenic mechanism that operates during neuronal development and is based on the interaction of tumor necrosis factor receptor-associated factor 6 (TRAF6) with the synaptic cell adhesion molecule neuroplastin. The interaction between these proteins was predicted in silico and verified by co-immunoprecipitation in extracts from rat brain and co-transfected HEK cells. Binding assays show physical interaction between neuroplastin's C-terminus and the TRAF-C domain of TRAF6 with a Kd value of 88 μM. As the two proteins co-localize in primordial dendritic protrusions, we used young cultures of rat and mouse as well as neuroplastin-deficient mouse neurons and showed with mutagenesis, knock-down, and pharmacological blockade that TRAF6 is required by neuroplastin to promote early spinogenesis during in vitro days 6-9, but not later. Time-framed TRAF6 blockade during days 6-9 reduced mEPSC amplitude, number of postsynaptic sites, synapse density and neuronal activity as neurons mature. Our data unravel a new molecular liaison that may emerge during a specific window of the neuronal development to determine excitatory synapse density in the rodent brain.

U2 - 10.3389/fcell.2020.579513

DO - 10.3389/fcell.2020.579513

M3 - SCORING: Journal article

C2 - 33363141

VL - 8

SP - 579513

JO - FRONT CELL DEV BIOL

JF - FRONT CELL DEV BIOL

SN - 2296-634X

ER -