Affiliation:
1. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
2. Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
Abstract
In cell culture, genetically identical cells often exhibit heterogeneous behavior, with only ‘lineage primed’ cells responding to differentiation inducing signals. It has recently been proposed that such heterogeneity exists during normal embryonic development to allow position independent patterning based on ‘salt and pepper’ differentiation and sorting out. However, the molecular basis of lineage priming and how it leads to reproducible cell type proportioning are poorly understood. To address this, we employed a novel forward genetic approach in the model organism Dictyostelium discoideum. These studies reveal that the Ras-GTPase regulator gefE is required for normal lineage priming and salt and pepper differentiation. This is because Ras-GTPase activity sets the intrinsic response threshold to lineage specific differentiation signals. Importantly, we show that although gefE expression is uniform, transcription of its target, rasD, is both heterogeneous and dynamic, thus providing a novel mechanism for heterogeneity generation and position-independent differentiation.
Funder
Wellcome Trust
Lister Institute of Preventive Medicine
Natural Environment Research Council
Royal Society Wolfson Merit
Medical Research Council
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
17 articles.
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