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Engineering Synthetic Morphogen Systems that Can Program Multicellular Patterning

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One of the core processes of development biology involves establishing positions of various cells within a tissue, called morphogenesis. DARPA BETR performers at @UCSF recently demonstrated in @ScienceMagazine that synthetic green fluorescent protein (GFP) signals can be substituted for a natural morphogen to organize patterning.

The BETR program aims to provide medical interventions with the necessary sophistication to more quickly restore complex human tissues after injury. The effort notably focuses on injuries relevant to the warfighter such as blast and burn damage to bone, skin, and nerves. If the program succeeds, warfighters could return to duty sooner and more fully healed:

Morphogens provide positional information during tissue development. For this behavior to occur, morphogens must spread out and form a concentration gradient; however, their mechanism of transport remains a matter of debate. Stapornwongkul et al. now show that in the presence of extracellular binding elements (binders), the inert green fluorescent protein (GFP) can form a detectable concentration gradient by diffusion in the developing fly wing (see the Perspective by Barkai and Shilo). When combining the expression of nonsignaling binders and receptors engineered to respond to GFP, a synthetic GFP gradient can substitute for a natural morphogen to organize growth and patterning. In related work, Toda et al. also show that GFP can be converted into a morphogen by providing anchoring interactions that tether the molecule, forming a gradient that can be recognized by synthetic receptors that activate gene expression. These synthetic morphogens can be used to program de novo multidomain tissue patterns. These results highlight core mechanisms of morphogen signaling and patterning and provide ways to program spatial tissue organization independently from endogenous morphogen pathways.

In metazoan tissues, cells decide their fates by sensing positional information provided by specialized morphogen proteins. To explore what features are sufficient for positional encoding, we asked whether arbitrary molecules (e.g., green fluorescent protein or mCherry) could be converted into synthetic morphogens. Synthetic morphogens expressed from a localized source formed a gradient when trapped by surface-anchoring proteins, and they could be sensed by synthetic receptors. Despite their simplicity, these morphogen systems yielded patterns reminiscent of those observed in vivo. Gradients could be reshaped by altering anchor density or by providing a source of competing inhibitor. Gradient interpretation could be altered by adding feedback loops or morphogen cascades to receiver cell response circuits. Orthogonal cell-cell communication systems provide insight into morphogen evolution and a platform for engineering tissues.

https://science.sciencemag.org/content/370/6514/327