Dr. Paul Langridge

Post-Doctoral Training

Columbia University, New York                                      
Department of Genetics and Development

Teaching Area

Principles of biology I
Biomolecular techniques 6170
Principles of biology lab Bio1107L

Research Interests

Mechanosensitive ligand/receptor bridges 

One way cells communicate is through physical contact. For example, a protein on the surface of one cell can act as a signal or ligand and contact its specific receptor on the surface of another cell. A ligand/receptor bridge that links cells in this way can communicate vital information about the position of a cell relative to its neighbors, what sort of function the cell should adopt, whether a cell should begin moving or growing, or whether two neurons should form a synapse.

An important signaling pathway in biology involves the Notch receptor. All animals have Notch receptors and they are central to many developmental and physiological processes. Dysregulation of Notch is also the cause of many developmental abnormalities and diseases, including severe forms of cancer. Notch is particularly interesting because it is a mechanosensitive receptor: When ligand makes contact with Notch, it ‘pulls’ on the receptor and initiates receptor activation. We are exploring ligand/receptor bridges like these in vivo using the powerful Drosophila tools we have developed to manipulate ligand/receptor interactions. The work has the potential to shed further light on the activation of the Notch receptor and reveal general principles that will be applicable to ligand/receptor bridges formed by other proteins and in many different contexts.

Ectopic Notch activation in the developing wing disc. Where the blue ligand presenting cells meet the uncolored receptor presenting cells, there is a burst of receptor activation and the expression of target genes (yellow).

Developing a platform for engineering customizable cell-cell signaling in vivo 

Our work has potential future applications in synthetic biology. Synthetic biology combines biological and engineering principles to regulate cellular processes, and is emerging as an important area of biomedical research. To date synthetic biology has focused largely on manipulating processes inside cells, most notably to control gene expression or metabolism, and arranging them into modules that perform discrete functions. By contrast, current cell-culture based synthetic approaches are ill-equipped to manipulate processes that control interactions between cells to create desired outcomes at the tissue level, a capacity that would be of particular value in the fields of tissue engineering and regenerative medicine. What is needed is a genetically tractable in vivo platform within which synthetic cell-cell signaling tools can be rapidly created, tested, optimized and diversified, before they are deployed and further refined in systems that have therapeutic and biotechnological applications. We aim to fulfill this requirement by establishing a Drosophila system for designing synthetic intercellular signaling that controls tissue behavior. We have developed prototype synthetic ligand/receptor systems predicated on the basic mechanism of Notch activation. We are using this tractable in vivo system for developing cell-cell signaling technology that has future applications in tissue engineering and regenerative medicine.

Receptor responses can be customized. In the above image, the blue ligand cells confront the red receptor cells and the receptor is activated. This synthetic receptor has a transcription factor domain that causes the expression of GFP (green) in the signal receiving cells.

Publications  

Langridge, P. D., Chan, J., Garcia-Diaz, A., Greenwald, I. & Struhl, G. (2021) The C. elegans Notch proteins LIN-12 and GLP-1 are tuned to lower force thresholds for activation than Drosophila Notch BioRxiv2021.02.11.429991 [Preprint]. February 11 2021. Available from:https://doi.org/10.1101/2021.02.11.429991.

Langridge, P. D.* and Struhl, G.* (2017) Epsin-dependent ligand endocytosis activates Notch by force. Cell, 171 (6) 1383–1396.

Kay, R. R., Langridge, P. D., Traynor, D., and Hoeller, O.* (2008) Changing directions in the study of chemotaxis. Nature Reviews in Molecular Cell Biology, 9 (6) 455-63.

Langridge, P. D.* and Kay, R. R. (2007) Mutants in the Dictyostelium Arp2/3 complex and chemoattractant-induced actin polymerization. Experimental Cell Research, 313 (12) 2563-2574.

Langridge, P. D.* and Kay, R. R. (2006) Blebbing of Dictyostelium cells in response to chemoattractant. Experimental Cell Research, 312 (11) 2009-2017.