K252A promotes neuronal survial

K252A promotes neuronal survial - A Novel p75NTR Signaling...

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Unformatted text preview: A Novel p75NTR Signaling Pathway Promotes Survival, Not Death, of Immunopurified Neocortical Subplate Neurons Michael F. DeFreitas, 1 Patrick S. McQuillen, 2 and Carla J. Shatz 1 1 Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and 2 Department of Pediatrics, University of California, San Francisco Medical Center, San Francisco, California 94143 Subplate neurons of mammalian neocortex undergo pro- nounced cell death postnatally, long after they have matured and become incorporated into functional cortical circuits. They express the p75 neurotrophin receptor (p75NTR), which is known to signal cell death in some types of neurons via the activation of sphingomyelinase and the concomitant increase in the sphingolipid ceramide. To evaluate the role of p75NTR in subplate neurons, they were immunopurified and cultured in vitro . Contrary to its known function as a death receptor, ligand binding to p75NTR promotes subplate neuron survival. More- over, p75NTR-dependent survival is blocked by inhibition of ceramide synthesis and rescued by addition of its precursor sphingomyelin. Inhibition of Trk signaling does not block sur- vival, nor is Trk signaling alone sufficient to promote survival. Thus, ligand-dependent p75NTR regulation of the ceramide pathway mediates survival in certain neurons and may repre- sent an important target for neuroprotective drugs in degener- ative diseases involving p75NTR-expressing neurons, such as Alzheimer’s disease. Key words: subplate neurons; p75 neurotrophin receptor; survival; ceramide; BDNF; immunopurification Subplate neurons are among the earliest-generated neurons of developing cerebral cortex and form the deepest layer below the developing cortical plate (Allendoerfer and Shatz, 1994). They are the first cortical neurons to differentiate and become incor- porated into functional neuronal circuits, where they are needed for the establishment of thalamocortical connections (Friauf et al., 1990; Ghosh et al., 1990; Ghosh and Shatz, 1993). However, unlike later-generated cortical neurons, large numbers of subplate neurons undergo programmed cell death during early postnatal development (Allendoerfer and Shatz, 1994; Spreafico et al., 1995; Price et al., 1997). This raises the question of how a mature population of CNS neurons that is fully integrated into a func- tioning circuit are selectively eliminated, and conversely, what signal transduction pathways control their survival. Neuronal survival throughout the peripheral nervous system (PNS) is primarily controlled by neurotrophins interacting with two types of neurotrophin receptors: the ligand-selective Trk tyrosine kinases and the nonselective p75 neurotrophin receptor (p75NTR) (Barbacid, 1995; Conover and Yancopoulos, 1997; Chao et al., 1998). Trk receptors play a critical role in promoting the survival of many PNS neurons via activation of their tyrosine kinase domains. In contrast, the role of p75NTR in neuronal survival is cell-type dependent. From studies of knock-out mice,survival is cell-type dependent....
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K252A promotes neuronal survial - A Novel p75NTR Signaling...

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