Title:

Signal transduction

Description:  To investigate the transition from growth to multicellular differentiation,we have chosen the discoidin gene family as a molecular marker.
Author:C. Zeng, C. Anjard and W. Nellen
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Signal transduction


Dictyostelium feeds as single, amoeboid cells on bacteria. When the food source is exhausted, cells stop vegetative growth (cell division) and enter a developmental cycle. They secrete cAMP which serves as a signal for the cells to stream together and form aggregates of approx. 100.000 individuals. In the aggregates, cells eventually differentiate into non-viable stalk- and dormant spore-cells.

To investigate the transition from growth to multicellular differentiation,we have chosen the discoidin gene family as a molecular marker.

The discoidins are cytoplasmic proteins which are not essential for growth or development (under laboratory conditions) but appear to be involved in cell shape changes at the onset of development: during growth, cells are more or less round, when starved, they elongate and obtain a pronounced anterior-posterior polarity. Strains which do not express discoidins have problems with the organization of migration streams towards aggregation centers.

Discoidins are expressed several generations before the food source is exhausted. Gene expression is induced at low levels by a secreted factor (PSF) which enables the cells to measure their own density in relation to the available food supply.

A second boost of induction (developmental induction) begins approximately 2 hours after starvation.

At about 6 hours of development, discoidin expression is downregulated by cAMP.

Using mutants in known signal transduction components, the following pathways have been established:

  1. Developmental induction requires an unknown cell surface receptor coupled to the G-protein alpha 2. The signal is then transduced to the cytosolic regulator of adenylyl cyclase (CRAC). Surprisingly, the most abundant cyclase ACA is not required for the following events even though intracellular cAMP is sufficient to activate protein kinase A (PKA) and finally induce transcription.

  2. Repression of the discoidins is mediated by extracellular cAMP via the serpentine surface receptor cAR1. Apparently, coupling to G-proteins is not essential. Stimulation of the receptor can cause an influx of calcium which eventually leads to a shut-off of discoidin transcription.

Thus there is the interesting situation that intracellular cAMP can stimulate while extracellular cAMP can represses discoidin expression. Circumstantial evidence suggests, however, that PKA may be induced by other signal molecules in addition to cAMP.

To fill in the gaps in this signalling cascad and in order to understand the mechanisms controlling the growth-development-transition (GDT), we have generated a number of mutants by REMI (restriction enzyme mediated integration) which misregulate discoidin expression. We have identified several mutants which display no or weak discoidin expression and others which show dramatic overexpression.

gdt1 was the first gene isolated from an overexpression mutant. The gene encodes a transmembrane protein which serves as a negative regulator of the GDT (see Zeng, Changjiang Thesis, Kassel-University-Press (1998), C. Zeng et al., Molecular Biology of the Cell, 11, 1631-1643, 2000). The gdt1 gene product gdt1p is a target of PKA in vitro and it appears that the protein is inactivated by phosphorylation (C. Zeng et al., Differentiation, 2001 in press). This and further genes which are currently under investigation are summarized in our current model.

  
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We are grateful to C. Zeng, C. Anjard and W. Nellen for contributing this article.

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