Biology subjects

Fisher, K. H.

Publications and source records attributed to Fisher, K. H..

3 recordsLinked to original sources

bioRxiv2017

Information Flow in Planar Polarity

In developing tissues, sheets of cells become planar polarised, enabling coordination of cell behaviours. It has been suggested that signalling of polarity information between cells may occur either bidirectionally or monodirectionally between the molecules Frizzled (Fz) and Van Gogh (Vang). Using computational modelling we find that both bidirectional and monodirectional signalling models reproduce known non-autonomous phenotypes derived from patches of mutant tissue of key molecules, but predict different phenotypes from double mutant tissue, which have previously given conflicting experimental results. Consequently, we re-examine experimental phenotypes in the Drosophila wing, concluding that signalling is most likely bidirectional. Our modelling suggests that bidirectional signalling can be mediated either indirectly via bidirectional feedbacks between asymmetric intercellular protein complexes, or directly via different affinities for protein binding in intercellular complexes, suggesting future avenues for investigation. Our findings offer insight into mechanisms of juxtacrine cell signalling and how tissue-scale properties emerge from individual cell behaviours.

systems biology↗

bioRxiv2017

A genome-wide RNAi screen identifies MASK as a positive regulator of cytokine receptor stability

In order for cells to sense and thus respond to their environment, they require transmembrane receptors, which bind extracellular ligands and then transduce this signal within the cell. A subset of receptors, with single-pass transmembrane domains are known as cytokine receptors and act via the Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT) pathway. These receptors are essential for processes such as haematopoiesis, immune responses and tissue homeostasis. In order to transduce ligand activation, cytokine receptors must dimerise. However, mechanisms regulating their dimerisation are largely unknown. In order to better understand the processes regulating cytokine receptor levels, activity and dimerisation, we used the highly conserved JAK/STAT pathway in Drosophila, which acts via a single receptor, known as Domeless. We have performed a genome-wide RNAi screen in Drosophila cells, identifying MASK as a positive regulator of Domeless dimerisation and protein levels. We show that MASK is able to regulate JAK/STAT signalling both in vitro and in vivo. We go on to show that MASK is able to bind to Domeless via its Ankyrin repeat domains and alters the stability of the receptor. Finally, we extend our observations to the human homologue, ANKHD1, and demonstrate functional conservation, with ANKHD1 able to regulate JAK/STAT signalling and the levels of a subset of pathway receptors in human cells. Taken together, we have identified MASK as a conserved regulator of cytokine receptor levels, which may have implications for human health.

cell biology↗

bioRxiv2017

Integrating Planar Polarity And Tissue Mechanics In Computational Models Of Epithelial Morphogenesis

Cells in many epithelial tissues are polarised orthogonally to their apicobasal axis. Such planar polarity ensures that tissue shape and structure are properly organised. Disruption of planar polarity can result in developmental defects such as failed neural tube closure and cleft palette. Recent advances in molecular and live-imaging techniques have implicated both secreted morphogens and mechanical forces as orienting cues for planar polarisation. Components of planar polarity pathways act upstream of cytoskeletal effectors, which can alter cell mechanics in a polarised manner. The study of cell polarisation thus provides a system for dissecting the interplay between chemical and mechanical signals in development. Here, we discuss how different computational models have contributed to our understanding of the mechanisms underlying planar polarity in animal tissues, focusing on recent efforts to integrate cell signalling and tissue mechanics. We conclude by discussing ways in which computational models could be improved to further our understanding of how planar polarity and tissue mechanics are coordinated during development.

systems biology↗