Proneural Basic Helix-Loop-Helix Proteins and Epidermal Growth Factor Receptor Signaling Coordinately Regulate Cell Type Specification and cdk Inhibitor Expression during Development

Abstract

Cell differentiation and cell cycle exit are coordinately regulated during development; however, the molecular logic underlying this regulation is not known. The Drosophila cdk inhibitor Dacapo (Dap) is one of the key cell cycle regulators that exhibit dynamic expression during development and contribute to the developmental regulation of the cell cycle. In this study, regulation of Dap expression during cell type specification was investigated. The expression of Dap in the R2 and R5 precursors of the developing eye and in the newly recruited leg disc femoral sense organ precursors was found to be controlled by the epidermal growth factor receptor signaling-regulated transcription factor Pointed (Pnt) and the proneural basic helix-loop-helix proteins Atonal (Ato) and Daughterless (Da). We show that Pnt, Ato, and Da regulate Dap expression directly through their respective binding sites precisely at the time when these transcription factors function to specify neural fates. These results show that Dap expression is directly regulated by developmental mechanisms that simultaneously control cell type specification. This is potentially a general mechanism by which the expression of key cell cycle regulators is coordinated with differentiation during normal development. The direct regulation of key cell cycle regulators by the differentiation factors ensures coordinated regulation of cell cycle and differentiation.

We thank H. Vaessin, I. Rebay, N. Baker, K. Cadigan, and the Drosophila Stock Center at Bloomington for fly stocks; Y. N. Jan, I. Hariharan, J. Skeath, K. Saigo, and the Iowa Developmental Studies Hybridoma Bank for antibodies; and J. Posakony for the pHStinger vector.

This work is supported by grants from NIH and ACS to W.D. W.D. is a Leukemia and Lymphoma Society scholar.