Editors' ChoiceNeuroscience

Transcription Factor for p75NTR

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Science Signaling  10 Feb 2009:
Vol. 2, Issue 57, pp. ec47
DOI: 10.1126/scisignal.257ec47

The p75 neurotrophin receptor (p75NTR) is a multifunctional molecule that interacts with various other receptors to control neuronal differentiation, migration, and survival. Pincheira et al. found with a two-hybrid screen with the death domain of p75NTR as bait that the transcription factor Sall2 interacted with the receptor. Sall2 was detected in most regions of the mouse brain and appeared to be present in neurons, not glial cells, where it colocalized with cells expressing p75NTR. Sall2 and p75NTR coimmunoprecipitated from mouse brain lysates, which suggests that the two proteins interacted in vivo. Studies in PC12 cells, a rat pheochromocytoma cell line that responds to nerve growth factor (NGF) and in which both p75NTR and the TrkA neurotrophin receptor are present, showed that under nonstimulated conditions Sall2 and p75NTR interacted and that stimulation with NGF promoted the dissociation of Sall2 from the receptor and its translocation into the nucleus (detected both biochemically and microscopically). When TrkA activity was absent or inhibited or when activation of the mitogen-activated protein kinases (MAPKs) ERK1 and 2 was inhibited, Sall2 failed to translocate to the nucleus in response to NGF treatment of PC12 cells. However, NGF also stimulated the increase in expression of the gene encoding Sall2, as well as the abundance of the protein, and this induction in Sall2 persisted even when the cells were deficient in TrkA activity. Knockdown experiments in PC12 cells and in primary hippocampal cells showed that Sall2 was necessary for full stimulation of neurite extension in response to NGF. Further knockdown experiments in the PC12 cells showed that Sall2 was necessary for full induction of the gene encoding p21WAF1/CIP1, a mediator of cell cycle arrest, in response to NGF and that overexpression of Sall2 was sufficient to inhibit cell division, as well as promote neurite extension. The authors propose that NGF stimulates the activity of TrkA, which activates the MAPKs ERK1 and 2, triggering the phosphorylation and dissociation of Sall2 from the p75NTR to mediate neuronal differentiation through regulation of gene expression.

R. Pincheira, M. Baerwald, J. D. Dunbar, D. B. Donner, Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth. EMBO J. 28, 261–273 (2009). [PubMed]

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