It has previously been shown that cell density increases the specific enzyme activity of tyrosine hydroxylase (TH) in cultures of PC12 cells. The difference in TH activity was shown to be due to cell-cell contact rather than to diffusible factors released by the PC12 cells (C. Lucas, D. Edgar, and H. Thoenen (1979) Exp. Cell Res. 121, 79-86). We have extended these studies and demonstrated that TH is regulated at the transcriptional level. Cells were harvested from confluent high-density cultures and replated at either low (2 x 10(4) cells/cm2) or high density (5 x 10(5) cells/cm2). At low density, the mRNATH and TH enzyme activity decreased to low levels within several hours. The decrease in TH activity resulting from the loss of cell-cell contact appears to be an active process, as it occurs much more rapidly than would be expected from the turnover rate of the protein in cells cultured continuously at high density. In contrast to low-density cultures the mRNATH and TH activity levels in replated high-density cultures decreased only slightly and then increased four fold at the mRNATH and five fold at the TH activity levels as compared to low-density cultures 2 days after replating. The increase in mRNATH preceded the increase in TH activity by 1 day. Since alpha-amanitin inhibited the increase in TH levels, we conclude that cell-cell contact regulates TH in PC12 cells at the transcriptional level.