REGULATION OF REGIONAL DIFFERENCES IN THE DIFFERENTIATION OF CEREBRALCORTICAL-NEURONS BY EGF FAMILY-MATRIX INTERACTIONS

Both lineage-based and epigenetic regulation have been postulated as m echanisms to control the formation of discrete areas in the cerebral c ortex, but specific genes or signaling pathways that may be involved h ave yet to be defined, In this paper, we examine whether progenitors, isolated from the cerebral wall prior to neurogenesis, can respond to exogenous cues by adopting a region-specific phenotype, The expression of the limbic system-associated membrane protein (LAMP), a neuron-spe cific marker of limbic cortical areas, was monitored in cultured neuro ns arising from precursors harvested from presumptive perirhinal (limb ic) and sensorimotor (nonlimbic) zones at embryonic day 12 in the rat, Neuronal phenotype in all cultures was identified by expression of mi crotubule-associated protein-2 (MAP2), On a substrate of poly-lysine, over 80% of the precursors from the limbic area that differentiate int o neurons express a LAMP(+) phenotype. Approximately 20% of the neuron s generated from precursors of the sensorimotor region become LAMP(+). However, modification of the microenvironment had a significant effec t on the differentiation of the sensorimotor precursors. When the nonl imbic precursors are grown on Matrigel, there is a 2-fold increase in the number of MAP2(+)/LAMP(+) double-labeled neurons, Dissection of th e Matrigel components reveals that in combination with growth factor-d eficient Matrigel or collagen type IV, epidermal growth factor and tra nsforming growth factor-alpha increase LAMP expression in the sensorim otor population, Delaying the addition of growth factor until after mo st cell division had ceased failed to increase the number of LAMP(+) n eurons, Another growth factor in Matrigel, platelet-derived growth fac tor, does not produce the same effect, Our results indicate that local signals can regulate the differentiation of cortical progenitors, pro viding a potential mechanism for establishing an early commitment to s pecific regional phenotypes in the developing cerebral wail that relat e to future functional domains in the cortex.