Abstract
CD40-activated CD40L reverse signaling is a major physiological regulator of axon and dendrite growth from developing hippocampal pyramidal neurons. Here we have studied how CD40L-mediated reverse signaling promotes the growth of these processes. Cultures of hippocampal pyramidal neurons were established from Cd40−/− mouse embryos to eliminate endogenous CD40/CD40L signaling, and CD40L reverse signaling was stimulated by a CD40-Fc chimera. CD40L reverse signaling increased phosphorylation and hence activation of proteins in the PKC, ERK, and JNK signaling pathways. Pharmacological activators and inhibitors of these pathways revealed that whereas activation of JNK inhibited growth, activation of PKC and ERK1/ERK2 enhanced growth. Experiments using combinations of pharmacological reagents revealed that these signaling pathways regulate growth by functioning as an interconnected and interdependent network rather than acting in a simple linear sequence. Immunoprecipitation studies suggested that stimulation of CD40L reverse signaling generated a receptor complex comprising CD40L, PKCβ, and the Syk tyrosine kinase. Our studies have begun to elucidate the molecular network and interactions that promote axon and dendrite growth from developing hippocampal neurons following activation of CD40L reverse signaling.
Highlights
The growth and elaboration of neural processes during development and maturity have a major bearing on the establishment and modification of the functional properties of neural circuits
The role CD40L reverse signaling in promoting dendrite and axon growth from hippocampal pyramidal neurons is based on the previously reported complete rescue of the reduced growth phenotype of cultured Cd40−/− neurons with CD40-Fc and the replication of the phenotype of Cd40−/− neurons in Cd40+/+ neurons by treating them with soluble CD40L, which competes with endogenous membrane-integrated CD40L for binding to endogenous CD40 [18]
Given the extensive physiological importance of CD40L reverse signaling in regulating the growth and elaboration of neural processes in the developing nervous system, the aim of the current study was to extend our understanding of the intracellular signaling events that mediate the effect of CD40L reverse signaling on axon and dendrite growth, focusing in on the well-characterized hippocampal pyramidal neuron model
Summary
The growth and elaboration of neural processes during development and maturity have a major bearing on the establishment and modification of the functional properties of neural circuits. In addition to intrinsic developmental programs in neurons and the pattern of electrical activity, a wide variety of extrinsic signals orchestrate the growth, elaboration and remodeling of axons and dendrites, including deltanotch, Eph-Ephrins, cell adhesion molecules, neurotrophins, semaphorins, and slits [1, 2]. One of the latest groups of proteins recognized to influence the growth of neural processes during development is the tumor necrosis factor superfamily (TNFSF). Bidirectional signaling between membrane-integrated CD40 ligand (CD40L, TNFSR5) and CD40 (TNFRSF5) is a important physiological regulator of axon and dendrite growth in many populations of neurons in the developing nervous system. In vivo analysis of wild type and Cd40−/− mice together with a variety of in vitro experiments have demonstrated that CD40L-activated CD40-mediated forward signaling promotes early sensory axon growth [20], whereas CD40-activated CD40L-mediated reverse signaling
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