Research

Signal Transduction
Cell cycle control and cell differentiation

Research Interest:

All cells respond to extracellular signals, and these signals are transmitted through highly-conserved biochemical pathways, termed signal transduction pathways, to generate a cellular response. In fact, most cellular responses are controlled by several different signals and signaling pathways, raising the question of how different signaling pathways can be integrated together to control a single response. To address this question, we make use of a simple model system: the switch between mitotic growth and meiotic differentiation in the yeast S. cerevisiae. Diploid yeast switch between these two alternative pathways based on several different nutritional signals. These signals are of two types: 1) regulators present in growing cells act to repress meiotic differentiation; for example, Cln cyclins repress transcription of meiotic genes, and 2) specific nutritional signals may either inhibit or promote meiosis; for example, glucose inhibits meiosis whereas acetate activates the meiotic program.

Fig. 1 The meiosis/mitosis switch. Legend

Glucose acts through the Snf1 kinase glucose-repression pathway, whereas the pathway that transmits the acetate signal remains unknown. The focus of my lab is on the ways in which growth, glucose and acetate signaling pathways are integrated together to control the choice between meiosis and mitosis.

Our experimental approach combines molecular biology, cell biology, and genetics. Several "rules" of signal pathway integration are emerging from this work.

Fig. 2 Synaptonemal complex formation demarcates early and late meiotic controls. Legend

1) Extracellular signals can control the choice between growth and differentiation at more than one stage of differentiation. Initially, nutrients control entry of cells into the meiotic pathway by regulating transcription of IME1 and IME2. Expression of these two genes triggers the early stages of meiosis, for example meiotic replication and recombination. Separately from these early controls, nutrients also regulate entry into the late stages of meiosis, for example, the two meiotic divisions and spore formation. One consequence of this dual control is that under some circumstances yeast can complete early stages of meiosis and then return to the mitotic cell cycle.

2) Combinations of signals which promote neither growth nor differentiation cause cells to express moderate levels of the genes that regulate differentiation. Moderate levels of IME1 and IME2 expression are not sufficient to trigger meiosis but serve to potentiate meiotic differentiation once additional nutritional signals are received. This potentiated state may be maintained through negative feedback control on IME1.

autorad gel
Fig. 3 IME1 transcript is regulated at three distinct levels. Legend

3) Different signals can be ordered hierarchically within a regulatory logic circuit. For example, acetate promotes meiosis only after cells have stopped growing; thus, repression of meiosis in growing cells has precedence over induction of meiosis by acetate. The molecular basis for this hierarchy may be that growth represses the initial stage of IME1 induction, whereas nutritional signals both induce IME1 and release the negative loop.

simple diagram
Fig. 4 Working model for integration of glucose and cell cycle controls on IME1 transcript levels. Legend

Research Support

This research is supported by a grant from the National Institutes of Health.