Sensory neurons although it mediates naturally

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sensory neurons, although it mediates naturally occurring cell death of sympathetic and certain motor neurons (Lee et al., 1992; Bamji et al., 1998; Brennan et al., 1999; Frade and Barde, 1999). In vitro , p75NTR has been found to mediate neuronal survival by facilitating Trk signaling at low neurotrophin concentrations (Da- vies et al., 1993; Lee et al., 1994). Death, on the other hand, is thought to result from p75NTR signaling in the absence of Trk activation (Carter and Lewin, 1997; Dechant and Barde, 1997; Yoon et al., 1998). This leads to ceramide production, which in turn activates an apoptotic signaling cascade (Casaccia-Bonnefil et al., 1996; Hannun, 1996). Analysis of mice deficient in neurotrophins or their receptors also argues for neurotrophin-dependent survival of certain pop- ulations of cerebral cortical neurons (Minichiello and Klein, 1996; Alca´ntara et al., 1997; Chen et al., 1997; Fagan et al., 1997; Peterson et al., 1999). However, because neurotrophins also reg- ulate axon outgrowth, it is unclear from these in vivo studies whether the neurotrophins and their receptors promote survival by acting directly on the neurons of interest, or whether they indirectly promote survival by affecting other cell types or even target innervation. p75NTR, as well as TrkB, is expressed by subplate neurons (Allendoerfer et al., 1990; Cabelli et al., 1996). Whereas TrkB is also expressed by neurons of all other cortical layers, p75NTR expression within developing neocortex is highly restricted to the subplate (Koh and Loy, 1989; Allendoerfer et al., 1990; Meinecke and Rakic, 1993). Given the link between p75NTR and cell death in the PNS (Carter and Lewin, 1997; Dechant and Barde, 1997; Chao et al., 1998), we hypothesized that the selective loss of subplate neurons could be explained by the restricted expression of p75NTR and activation of its associ- ated apoptotic signaling pathways. To study the role of p75NTR and its associated signal transduction pathways on subplate neu- ron survival, we used immunopanning techniques to purify these neurons. This novel purification of subplate neurons allowed us to Received Oct. 17, 2000; revised March 1, 2001; accepted May 1, 2001. This research was supported by National Eye Institute Grants EY02858 (C.J.S.) and F32 EY06602 (M.F.D.), National Institutes of Health Grant K12HD00850 (P.S.M.), and University of California, San Francisco Child Health Research Cen- ter–National Institute of Child Health and Human Development Grant HD28825-07 (P.S.M.). We thank Louis Reichardt, Eric Shooter, and MarkBothwell for the anti-p75NTR antibodies, Cynthia Cowdrey for preparing the cryostat sections, Claire McKellar for assisting with subplate purifications, Ben Barres for technical advice on the immunopanning protocol, and both Ben Barres and Michael Green- berg for reading this manuscript and providing valuable feedback. Correspondence should be addressed to Carla J. Shatz, Department of Neurobi- ology, Harvard Medical School, 220 Longwood Avenue, 405 Goldensen Building, Boston, MA 02115. E-mail: [email protected]
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