Central nervous system (CNS) development is highly guided by microenvironment cues specially provided by neuron-glia interactions. By using a transgenic mouse bearing part of the gene promoter of the astrocytic maturation marker GFAP (glial fibrillary acidic protein) linked to the beta-galactosidase (beta-Gal) reporter gene, we previously demonstrated that cerebral cortical neurons increase transgenic beta-Gal astrocyte number and activate GFAP gene promoter by secretion of soluble factors in vitro. Here, we identified TGF-beta1 as the major mediator of this event. Identification of TGF-beta1 in neuronal and astrocyte extracts revealed that both cell types might synthesize this factor, however, addition of neurons to astrocyte monolayers greatly increased TGF-beta1 synthesis and secretion by astrocytes. Further, by exploiting the advantages of cell culture system we investigated the influence of neuron and astrocyte developmental stage on such interaction. We demonstrated that younger neurons derived from 14 embryonic days wild-type mice were more efficient in promoting astrocyte differentiation than those derived from 18 embryonic days mice. Similarly, astrocytes also exhibited timed-schedule developed responsiveness to neuronal influence with embryonic astrocytes being more responsive to neurons than newborn and late postnatal astrocytes. RT-PCR assays identified TGF-beta1 transcripts in young but not in old neurons, suggesting that inability to induce astrocyte differentiation is related to TGF-beta1 synthesis and secretion. Our work reveals an important role for neuron-glia interactions in astrocyte development and strongly implicates the involvement of TGF-beta1 in this event.