The extracellular matrix protein tenascin (TN) is expressed with precise temporo-spatial patterns during embryonic and fetal development and is induced in healing wounds, inflammatory lesions and solid tumors. These tissue patterns suggest that TN synthesis may be modulated by soluble factors present in developing tissues or released from injured, inflammatory or neoplastic cells. To characterize the extrinsic control of human TN we examined the effects of several signalling molecules on cultured neural, melanocytic and fibroblastic cells. Results obtained with αTN antibodies in enzyme-linked immunosorbent and immunoprecipitation assays indicate that TN expression is tightly regulated in a cell type-specific manner: (1) Primitive neuroectodermal tumor (PNET) cells grown in chemically defined, serum-free media show up to >100-fold TN induction in response to fibroblast growth factors (aFGF, bFGF, K-FGF) and phorbol ester, independent of changes in cell proliferation or total protein synthesis; no induction is seen in PNET cultures stimulated with serum or other growth and differentiation factors. (2) Normal melanocytes, which require FGF and phorbol ester for survival in vitro, fail to express TN; however, they produce TN following oncogenic transformation. (3) Fibroblasts derived from disparate tissues differ up to 100-fold in basal TN production; for example, fetal lung fibroblasts are TN^high, but conjunctival fibroblasts derived from the same donors and fetal leptomeningeal cells are TN^low. (4) TN^lowfibroblasts treated with interleukin-1, tumor necrosis factor-α, and interleukin-4 show up to >100-fold increased TN secretion and TN incorporation into their extracellular matrix. Transforming growth factor-β, which acts as an inducer of fibronectin, collagen, and integrin-type matrix receptors, has variable effects on fibroblast TN, ranging from increased deposition in the extracellular matrix of fetal conjunctival fibroblasts to reduced secretion in newborn foreskin fibroblasts. In contrast, FGFs (which are potent fibroblast mitogens), phorbol ester, bone morpho-genetic proteins, and several other factors tested produced no discernible effects on fibroblast TN expression. These findings suggest that discrete sets of extrinsic signals modify TN expression in specific cell types, with the effects of a given ligand/receptor system determined by cell type-specific signalling pathways that may be linked to unique cis-regulatory elements of the TN gene. As a result, a limited set of regulatory peptides may produce highly diversified TN distribution patterns in developing and lesional tissues.