The p75 neurotrophin receptor acts as a "switch on-off" protein in early transit amplifying differentiation

p75 neurotrophin receptor (p75NTR), expressed in transit amplifying (TA) cells, mediates neurotrophin (NT) signals alone or in combination with the high affinity receptor Trk. In the present work, we studied the role of p75NTR during keratinocyte differentiation. p75NTR was up-regulated during keratinocyte differentiation in cell culture system both with serum and with calcium treatment. When p75NTR was silenced, calcium treatment failed to induce differentiation in subconfluent keratinocytes. In human skin, p75NTR is only expressed in the basal keratinocyte layer and is confined to a MIB-1 negative cell population. p75NTR+ cells, isolated by magnetic cell sorting, were less differentiated and proliferated less than p75NTR– cells in vitro, which in turn include keratinocyte stem cells (KSC), as shown by western blotting and confocal analysis. p75NTR+ keratinocytes, isolated from TA cells, expressed more survivin and CK15, while displayed less CK10 than p75NTR- TA. Colony forming efficiency and long term proliferation analysis revealed that p75NTR+ TA yielded a higher number of cells than p75NTRTA, suggesting that p75NTR+ cells are early TA cells. p75NTR retroviral infection of KSC induced a more differentiated phenotype, with the same features of TA cells. Finally, skin reconstructs originated from TA p75NTR- cells generated a hyperproliferative phenotype. These results suggest that p75NTR+ keratinocytes represent a subpopulation of TA cells, directly derived from stem cells that just started the differentiation process. p75NTR may act as a “switch on-off” protein in stem-TA transition, initiating keratinocyte differentiation.