New evidence challenges thinking on long range Wnt signalling

02 January 2014

Research by scientists from NIMR challenges the accepted notion that Wnts need to spread to control growth and patterning. The work is published in Nature.

Wnts are secreted signaling proteins that, during development, spread from their site of synthesis to form a gradient and activate target gene expression at a distance. They control patterning and growth during development. Long-range Wnt activity has been most extensively studied in wing imaginal discs of Drosophila.

During early larval life, Wingless, the main Drosophila Wnt, is initially expressed throughout the prospective wing field to establish wing primordium. At subsequent stages, Wingless is produced in a narrow stripe of cells and is thought to spread throughout the prospective wing blade, thus activating target gene expression in a concentration-dependent manner. It is generally accepted that Wingless needs to spread over the whole wing field for patterning and growth, but this has never been directly tested.

Cyrille Alexandre and Alberto Baena-Lopez

Cyrille Alexandre and Alberto Baena-Lopez

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Cyrille Alexandre and Alberto Baena-Lopez (pictured above), in Jean-Paul Vincent's lab in NIMR’s Division of Developmental Biology, used genome engineering to modify the endogenous wingless gene, which encodes the main Drosophila Wnt, so that it would express a membrane-tethered form of the protein.

Surprisingly, the resulting flies were viable and produced normally patterned wings of nearly the right size. Prolonged wingless transcription followed by memory of earlier signaling allowed persistent expression of relevant target genes, thus explaining why Wingless release is dispensable.

“Our results will come as a surprise to many, even though previous papers hinting that Wingless is not a morphogen can be found. Our finding changes radically our expectation of how Wnts control growth, patterning, regeneration and possibly stem cell niches

Jean-Paul Vincent

Our work has been made possible by long term investments in genomic engineering within the lab. So far, our results only apply to the main Wnt of Drosophila and we suggest that the requirement for long-range spreading of other Wnts could (and should) be assessed in other model organisms. Furthermore our genome editing approach and associated tools for mosaic analysis provide a template for further investigation of other signaling proteins.

Alberto Baena-Lopez

It will be exciting to figure out the molecular basis of signaling memory.

Cyrille Alexandre

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A stable reporter gene system (brown) shows that all the cells of the wing primordium or their ancestors express Wingless.

Original article

Cyrille Alexandre, Alberto Baena-Lopez, and Jean-Paul Vincent (2013)

Patterning and growth control by membrane-tethered Wingless

Nature, Epub ahead of print. Publisher abstract.

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