NGF Controls Dendrite Development in Hippocampal Neurons by Binding to p75^NTRand Modulating the Cellular Targets of Notch

Abstract

Notch and neurotrophins control neuronal shape, but it is not known whether their signaling pathways intersect. Here we report results from hippocampal neuronal cultures that are in support of this possibility. We found that low cell density or blockade of Notch signaling by a soluble Delta-Fc ligand decreased the mRNA levels of the nuclear targets of Notch, the homologues of enhancer-of-split 1 and 5 (Hes1/5). This effect was associated with enhanced sprouting of new dendrites or dendrite branches. In contrast, high cell density or exposure of low-density cultures to NGF increased the Hes1/5 mRNA, reduced the number of primary dendrites and promoted dendrite elongation. The NGF effects on both Hes1/5 expression and dendrite morphology were prevented by p75-antibody (a p75 NTR -blocking antibody) or transfection with enhancer-of-split 6 (Hes6), a condition known to suppress Hes activity. Nuclear translocation of NF-kappaB was identified as a link between p75 NTR and Hes1/5 because it was required for the up-regulation of these two genes. The convergence of the Notch and p75 NTR signaling pathways at the level of Hes1/5 illuminates an unexpected mechanism through which a diffusible factor (NGF) could regulate dendrite growth when cell-cell interaction via Notch is not in action.

The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons

“…In adult dorsal root ganglion neurons and postnatal cerebellar neurons, binding of myelinderived proteins to p75 NTR activates RhoA and thereby inhibits growth (Yamashita et al, 2002). Recent studies also suggest a multipotential role of p75 NTR in modulating dendrite morphology during development of hippocampal neuronal cultures, by either reducing the number of primary dendrites and by controlling the cellular targets of Notch (Salama-Cohen et al, 2005) or by mediating the filopodia growth promoting activity of TrkB-T1 (Hartmann et al, 2004). These and related observations suggest that the effects of p75 NTR strongly depend on the cellular context in which it is expressed and that, under certain cellular conditions, it can act antagonistically to the Trk receptors.…”

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…Previous work has demonstrated that Notch activation mediates changes in gene expression responsible for the contact-dependent inhibition of dendritic growth. 42 Using primary murine hippocampal cultures, Salma-Cohen et al 43 provided evidence that NF-kB activation downstream of NGF and the p75 NTR can regulate expression of some of the same transcripts as Notch. This pathway was suggested to function in parallel to Notch, and to allow modulation of dendrite growth by soluble factors even in the absence of cell-contact signals.…”

Notch activation induces neurite remodeling and functional modifications in SH‐SY5Y neuronal cells

“…Activated Notch receptor has been suggested to play a role in determining the only possible cell fate decision in postmitotic mature neurons, such as synaptic remodeling or neurite extension/retraction (Berezovska et al, 1999), as well as in the control of the branching points number according to the cell density and the specific cellular population (Sestan et al, 1999;Salama-Cohen et al, 2005). In the present study, we focused our attention on the varicosities, particular structures along the neurite that are believed to be hallmarks of the presynaptic compartment.…”

“…Notch pathway also controls the postsynaptic compartment by regulating dendrite outgrowth and branching (Redmond et al, 2000). Recent studies showed that stimulation of Notch by cell-cell contact or neurotrophic factors affects dendrite morphology and the ratio of excitatory/inhibitory synaptic terminals in hippocampal cultured cells (Salama-Cohen et al, 2005. Moreover, excitotoxic stimuli induced Notch protein activation in adult brain; this observation suggested us the possible Notch pathway involvement in degenerative processes Grilli et al, 2003).…”