CEREBRAL CORTICAL PROGENITORS ARE FATED TO PRODUCE REGION-SPECIFIC NEURONAL POPULATIONS

The mammalian cerebral cortex is characterized by its organization int o anatomically and functionally discrete regions. During cortical deve lopment, a homogeneous-appearing population of cells along the ventric ular surface generates the neurons and glia that ultimately form these cytoarchitectonic areas. The limbic system-associated membrane protei n (LAMP) is a neuronal, cell surface glycoprotein that identifies neur ons restricted to limbic cerebral cortical areas (Levitt, 1984). LAMP is expressed early in development (Horton and Levitt, 1988), and trans plantation studies in the rat suggest that cells in the cerebral wall are committed to a limbic or nonlimbic molecular phenotype by embryoni c day 14 (E14) (Barbe and Levitt, 1991). However, at E12, cells destin ed for the cerebral cortex are still multipotential and presumably dep end on local, extrinsic signals to adopt a limbic phenotype. We have d eveloped an in vitro assay system for examining the fate of these mult ipotential progenitors and identifying potential environmental regulat ors of neuronal differentiation. Regions of the lateral (limbic) and d orsal (nonlimbic) cerebral wall at E12 are dissected, dissociated, and grown in low-density cultures in defined medium. The cells are examin ed by immunocytochemistry for expression of MAP2, a neuronal cytoskele tal protein, and LAMP to define neuronal differentiation and the expre ssion of a limbic molecular phenotype, respectively. We find that afte r 4 d in culture, up to 75% of the progenitor cells from presumptive l imbic cortex express LAMP upon differentiation. In contrast, only 20-3 0% of the differentiated cells from presumptive sensorimotor cortex ex press LAMP. Thus, most cortical progenitors are fated to a limbic or n onlimbic phenotype early in development, and the decision by neuronal stem cells to differentiate into neurons exhibiting this molecular phe notype occurs prior to the completion of neurogenesis, in the absence of subcortical environmental cues.