Mice with a null mutation of the presenilin-1 (PS1-/-) gene die during late intrauterine life or shortly after birth and exhibit defects in cortical development. A previous report suggested that neurons differentiate prematurely in PS1-/- brain [M. Handler, X. Yang, J. Shen, Presenilin-1 regulates neuronal differentiation during neurogenesis, Development 127 (2000) 2593-2606]. Here we reexamined the issue of whether premature neuronal differentiation occurs in PS1-/- brain using fresh cell suspensions from embryonic E11.5 and E13.5 telencephalon where individual cell phenotypes can be easily determined with cell type specific markers. Immunostaining with seven neuronal specific markers (MAP2, beta-III tubulin, GABA, reelin, GluR2/3, calbindin, and calretinin) failed to reveal any evidence of premature neuronal differentiation in PS1-/- telencephalon. We also determined the fraction of cells expressing the neural progenitor marker nestin and found no evidence for premature depletion of neural progenitor cells in PS1-/- telencephalon. Moreover, based on MAP2 staining of tissue sections from E12.5 embryos the topography of newly generated neurons also appeared to be undisturbed in the telencephalon of PS1-/- embryos. These studies thus argue that premature neuronal differentiation is unlikely to be a core pathophysiological feature underlying the aberrant cortical development that occurs in PS1-/- brain.