Role of p75 neurotrophin receptor in stem cell biology: more than just a marker

Abstract

p75(NTR), the common receptor for both neurotrophins and proneurotrophins, has been widely studied because of its role in many tissues, including the nervous system. More recently, a close relationship between p75(NTR) expression and pluripotency has been described. p75(NTR) was shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. Here, we give an overview of the current knowledge on p75(NTR) in stem cells, ranging from embryonic to adult stem cells, and cancer stem cells. In an attempt to address its potential role in the control of stem cell biology, the molecular mechanisms underlying p75(NTR) signaling in different models are also highlighted. p75(NTR)-mediated functions include survival, apoptosis, migration, and differentiation, and depend on cell type, (pro)neurotrophin binding, interacting transmembrane co-receptors expression, intracellular adaptor molecule availability, and post-translational modifications, such as regulated proteolytic processing. It is therefore conceivable that p75(NTR) can modulate cell-fate decisions through its highly ramified signaling pathways. Thus, elucidating the potential implications of p75(NTR) activity as well as the underlying molecular mechanisms of p75(NTR) will shed new light on the biology of both normal and cancer stem cells.

Fig. 1

Schematic overview of p75^NTR interactions. p75^NTR can bind all neurotrophins and proneurotrophins, can dimerize, and can interact directly with Trk receptors, sortilin, Nogo-receptor, and Lingo1. The recruitment of intracellular proteins by p75^NTR activates downstream signaling cascades, leading to different biological responses. p75^NTR cleavage may also induce signaling mediated by the C-terminal fragment (CTF) or the intracellular fragment (ICD) of the receptor, generally leading to cell survival or apoptosis. ICD may be translocated to the nucleus to mediate its cellular responses (dotted arrows indicate that the exact molecular mechanisms leading to migration/invasion are unknown). In yellow are intracellular partners leading to pro-apoptotic signaling: NRAGE neurotrophin receptor-interacting MAGE homolog, NADE p75^NTR-associated cell death executor, NRIF neurotrophin receptor interacting factor, Rac1 Ras-related C3 botulinum toxin substrate 1, TRAF TNF receptor-associated factor. In pink are partners leading to pro-survival signaling: RIP2 receptor-interacting protein 2, FAP1 Fas-associated protein 1, FAIM Fas apoptosis inhibitor molecule, TRADD TNF receptor-associated death domain protein. In blue are partners leading to cell cycle arrest: SC1 Schwann cell factor-1, Sall2 Sal-like 2; Necdin. In green are partners related to neurogenesis and myelination: Par3 protease activated receptor 3, MAGI-1 membrane-associated guanylate kinase with inverted organization; Shc. In gray, PDE4 phosphodiesterase type 4, leading to cAMP degradation and matrix remodeling in Schwann cells

Fig. 2

p75^NTR-positive stem cells are present in many cellular models with different degrees of commitment. The fusion of gametes and formation of a diploid zygote determines the establishment of a multicellular embryo. Cells from the inner cell mass of the blastocyst (ESCs) present p75^NTR transcripts. p75^NTR-positive cells are present in multipotent migrating NCSCs (represented here during the neurulation stage) as well as in many fetal and post-natal tissues. It is worth noting that cell types other than neural crest-derived tissues present a subset of p75^NTR-positive stem cells, demonstrating a more primitive origin of these cells