Cell Fate Choices in the CNS

Abstract

During development, multipotent precursor cells differentiate into various cell types in response to different extracellular signals. Rajan et al. investigated the regulation of cell fate in central nervous system (CNS) stem cells, which can differentiate into non-CNS cell types when exposed to novel environments, and discovered that a single ligand, bone morphogenetic protein (BMP), could activate two distinct cell fate pathways. Rat CNS stem cells grown in culture without added BMP differentiated into CNS-type neurons or glia. Clonal cells treated with BMP differentiated into either glia or smooth muscle cells, depending on their local density. High-density cells differentiated into glia, whereas low-density cells differentiated into smooth muscle. Cells expressing a dominant-negative Smad protein mostly differentiated into glia upon BMP treatment, whereas cells expressing a dominant-negative STAT (signal transducer and activator of transcription) mostly differentiated into smooth muscle. The authors used a combination of Western analysis, electrophoretic mobility shift assays, and immunocytochemistry (on mouse cells) to show that BMP activated Smads in both high- and low-density cultures, whereas BMP treatment augmented basal STAT activation in high-density cultures. Pharmacologic analysis indicated that BMP4 activated STAT3 independently of transcription. Pharmacologic analysis, in combination with immunoprecipitation, and the expression of dominant negatives, indicated that the STAT pathway leading to glial differentiation depended on activation of the serine-threonine kinase FRAP (FKBP12/rapamycin-associated protein) secondary to dissociation of the immunophilin FKBP12 from the BMP receptor. Thus, BMP can stimulate differentiation down different cell fate pathways, depending on additional signals that influence the cytoplasmic environment. P. Rajan, D. M. Panchision, L. F. Newell, R. D. G. McKay, BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J. Cell Biol. 161 911-921 (2003). [Abstract] [Full Text]