During the development of a vertebrate nervous system, the cell fates are determined by a complex interaction between the intrinsic cellular program and signals in their local environment. These environmental signals include soluble factors, extracellular matrix and cell-cell interactions. As soluble factors, retinoic acid (RA) and neurotrophic factors (NTFs) have been suggested to play important roles in neurogenesis. However little is known on the molecular mechanism by which RA and NTFs induces neuronal differentiation in CNS. Using a human embryonal carcinoma cell line NTera2 cl. D1 as a model system, it is demonstrated that RA-induced neuronal differentiation might be mediated by the coordinated upregulation of the neurotrophin receptors. RA activates both the ras-dependent MAPK an...[ Read more ]

During the development of a vertebrate nervous system, the cell fates are determined by a complex interaction between the intrinsic cellular program and signals in their local environment. These environmental signals include soluble factors, extracellular matrix and cell-cell interactions. As soluble factors, retinoic acid (RA) and neurotrophic factors (NTFs) have been suggested to play important roles in neurogenesis. However little is known on the molecular mechanism by which RA and NTFs induces neuronal differentiation in CNS. Using a human embryonal carcinoma cell line NTera2 cl. D1 as a model system, it is demonstrated that RA-induced neuronal differentiation might be mediated by the coordinated upregulation of the neurotrophin receptors. RA activates both the ras-dependent MAPK and the JAK/STAT signaling cascade; sustained activation of the MAP kinases also reveals their potential roles in neuronal differentiation. Transcript analysis using RAP-PCR has led to the identification of candidate genes that are regulated during RA treatment. Besides the known cDNA sequences obtained such as the cellular retinoic acid binding protein and dystroglycan, four novel cDNA sequences are identified. One of the novel cDNA sequences, clone 29.2, encodes a putative protein kinase which might potentially be involved in both the neuronal development and functions. Although RA is required as a determinant, neuronal differentiation of NT2 cells could be modulated by other extrinsic factors such as cell-cell interaction and extracellular matrix provided by cell aggregation and laminin, respectively. Cell aggregation promotes the neuronal differentiation of NT2 cells whereas the presentation of the neuronal phenotypes is substrate-dependent.