Abstract
Dendrite size and morphology are key determinants of the functional properties of neurons and neural circuits. Here we show that CD40, a member of the TNF receptor superfamily, is a major regulator of dendrite growth and elaboration in the developing brain. The dendrites of hippocampal excitatory neurons were markedly stunted in Cd40-/- mice, whereas those of striatal inhibitory neurons were much more exuberant. These striking and opposite phenotypic changes were also observed in excitatory and inhibitory neurons cultured from Cd40-/- mice and were rescued by soluble CD40. The changes in excitatory and inhibitory neurons cultured from Cd40-/- mice were mimicked in neurons of Cd40+/+ mice by treatment with soluble CD40L and were dependent on PKC-β and PKC-γ, respectively. These results suggest that CD40-activated CD40L reverse signalling has striking and opposite effects on the growth and elaboration of dendrites among major classes of brain neurons by PKC-dependent mechanisms.
Highlights
The regulation of dendrite growth and elaboration during development has a major bearing on the functional properties of neurons and neural circuits, and many neurodevelopmental and acquired disorders of neural function are due primarily to structural abnormalities of dendrites and their connections (Penzes et al, 2011)
The reduced axon growth phenotype of neurons of Cd40-/- mice was completely rescued by CD40-Fc (p=2.6Â10À5, 3 days; p=4.9Â10À6, 9 days). These results suggest that CD40-activated CD40L-mediated reverse signalling enhances axon growth from developing hippocampal pyramidal neurons in culture
Because we have shown that activation of protein kinase C (PKC) is an essential step in the axon growth response of developing sympathetic neurons to TNFR1-activated TNFa-mediated reverse signaling (Kisiswa et al, 2017), we investigated whether PKC plays a role in mediating the divergent effects CD40-activated CD40L reverse signalling on dendrite growth in excitatory and/or inhibitory neurons
Summary
The regulation of dendrite growth and elaboration during development has a major bearing on the functional properties of neurons and neural circuits, and many neurodevelopmental and acquired disorders of neural function are due primarily to structural abnormalities of dendrites and their connections (Penzes et al, 2011). One of the latest groups of proteins recognized to modulate growth of neural processes during development is the tumor necrosis factor superfamily (TNFSF), the 19 members of which are best understood for their many roles in the immune system (Hehlgans and Pfeffer, 2005). They are active both as membrane-integrated ligands and as soluble ligands following cleavage from the cell membrane, and bind to one or more members of the TNF receptor superfamily (TNFRSF). Several studies have implicated TNFSF members in regulating the growth of neural processes in the developing CNS (Neumann et al, 2002; Osorio et al, 2014; Zuliani et al, 2006; McWilliams et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
