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First published online 24 April 2007
doi: 10.1242/jcs.003772

Journal of Cell Science 120, 1752-1762 (2007)
Published by The Company of Biologists 2007
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Research Article

Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis

Heather K. Bone and Melanie J. Welham*

Department of Pharmacy and Pharmacology and the Centre for Regenerative Medicine, University of Bath, Claverton Down, Bath, BA2 7AY, UK

* Author for correspondence (e-mail: M.J.Welham{at}bath.ac.uk)

Accepted 29 April 2007

Phosphoinositide 3-kinase (PI3K)-dependent signalling regulates a wide variety of cellular functions including proliferation and differentiation. Disruption of class IA PI3K isoforms has implicated PI3K-mediated signalling in development of the early embryo and lymphohaemopoietic system. We have used embryonic stem (ES) cells as an in vitro model to study the involvement of PI3K-dependent signalling during early development and haemopoiesis. Both pharmacological inhibition and genetic manipulation of PI3K-dependent signalling demonstrate that PI3K-mediated signals, most likely via 3-phosphoinositide-dependent protein kinase 1 (PDK1), are required for proliferation of cells within developing embryoid bodies (EBs). Surprisingly, the haemopoietic potential of EB-derived cells was not blocked upon PI3K inhibition but rather enhanced, correlating with modest increases in expression of haemopoietic marker genes. By contrast, PDK1-deficient EB-derived progeny failed to generate terminally differentiated haemopoietic lineages. This deficiency appeared to be due to a requirement for PI3K signalling during the proliferative phase of blast-colony-forming cell (BL-CFC) expansion, rather than as a result of effects on differentiation per se. We also demonstrate that PI3K-dependent signalling is required for optimal generation of erythroid and myeloid progenitors and their differentiation into mature haemopoietic colony types. These data demonstrate that PI3K-dependent signals play important roles at different stages of haemopoietic development.

Key words: PI3K, Embryoid bodies, Differentiation


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JCS 2007 120: 1003. [Full Text]  





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