The overall goal of research in the McNeill lab is to understand at a cellular level how tissue growth and tissue organization are regulated during normal development, and how loss of this control leads to human disease.

We use Drosophila and mouse genetics for in vivo analysis, as well as tissue culture and organoid approaches. One major focus of the lab is the investigation of Fat cadherins. Fat cadherins are enormous cell adhesion molecules that regulates cell proliferation, metabolism and cell polarity in all metazoa. We use Drosophila as a genetically tractable organism to investigate the basic and conserved mechanisms of Fat function and the control of Hippo pathway activity, and then extend our work to mammalian systems. Our most recent work has uncovered a novel and exciting role for Fat cadherins in regeneration.

We found that binding of Fat to its ligand Ds promotes Fat phosphorylation and signaling to the Hippo pathway. Now we are using proteomic screening to identify Fat cadherin pathway effectors, using BioID to identify interaction partners in a near physiological context. We also found that Ft cadherins undergo sequential cleavages release a cytosolic fragment that is imported into mitochondria (Fat-mito), where it binds Ndufv2, a component of CI.

Our work on Fat and the Hippo pathway in mouse models has revealed a critical and unsuspected role for the Hippo growth control pathway in morphogenesis. Using whole animal conditional and organ-culture approaches, we found that loss of NF2 or LATS or overexpression of YAP leads to growth and elongation of the collecting ducts in the absence of branching morphogenesis. To understand better how branching is affected, we will conduct high-resolution time-lapse imaging of the induction of branching morphogenesis. We will also assay tissue tension at junctions in the developing kidney with laser ablation and reporter assays.

In addition to our studies on Fat and the Hippo pathway, a new area of exciting research in the lab focuses on a novel nuclear membrane protein we isolated in genetic screens that we have found is essential for chromatin structure and fertility in flies, mice and fish. This project is taking us into exploring how changes in the nuclear envelope impact gene expression and cell fate.

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