Helen McNeill, PhD

Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor

Research interests

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

We investigate how these processes are regulated using both Drosophila and mouse genetics for in vivo analysis, as well as tissue culture and organoid approaches. The lab has a long tradition of investigating how Fat cadherins function in Hippo pathway-regulated growth control, planar cell polarity (PCP) tissue organization and metabolism.  Fat cadherins are enormous cell adhesion molecules that bind via cadherin-cadherin interactions to another large cadherin called Dachsous (Ds). The Hippo pathway is a highly conserved signaling pathway that regulates proliferation and apoptosis via control of the activity of the transcriptional co-activators Yorkie/YAP. 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. Our very recent work has uncovered a novel and exciting role for Fat cadherins in regeneration.

By studying Fat cadherins and the Hippo pathway in both fly and mouse models, we capitalize on each system’s strengths. We integrate biochemical studies with our genetic analysis to extend our knowledge and test our hypotheses. For example we used classical biochemical analysis to demonstrate that Fat is processed from a 560kDa precursor to a mature cell-surface receptor composed of a 110kDa transmembrane domain and a 450kDa extracellular domain composed of 34 cadherin repeats, EGF and LaminG domains that mediates binding to Ds. We showed binding of Fat to 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 showed 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. To identify the protease involved, we will now conduct a high throughput siRNA screen to identify genes essential for the mitochondrial localization of Fat/Fat4.

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 bud, and the trunk of developing.

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 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.

Lab website

Back Row: Daniel Potter, Didier Hodzic, Megan Glaeser, Alexander Fulford

Front Row: Jannette Rusch, Helen McNeill, Chloe Potter

Education and Professional Experience

Professor, Institute of Medical Science, University of Toronto, January 2011 – present

Professor, Department of Molecular Genetics, University of Toronto, July 2010 – present

Senior Investigator, Lunenfeld-Tanenbaum Research Institute (formerly, Samuel Lunenfeld Research Institute), Sinai Health System (formerly, Mount Sinai Hospital), September 2005- present

Professor of  Developmental Biology, Washington University School of Medicine, January 2018- present

Honors and Awards

2017- Fellow of the Royal Society of Canada

2016-present Canada Research Chair, Tier 1, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada

2012-present – Editorial Board Member, eLife, UK

2010 – The Lloyd S.D. Folger, Award for Research Excellence

2010 – Faculty of 1000 Reviewer, Faculty of 1000 Ltd, UK

2009-2012 – Member and the Representative of Canada, North American Drosophila Board of Directors

2007-2013 – Director of Collaborative Program in Developmental Biology,
University of Toronto, Canada

2006-2007 – Petro Canada Young Innovator’s Award, Petro Canada, Canada

2007-2012 –  Editorial Board Member, Developmental Dynamics, USA

1993-1996 –   Postdoctoral Fellowship, American Cancer Society, USA

1991-1992 –  Eloise Gerry Predoctoral Fellowship, Stanford University, USA

1991 – Katherine McCormick Fellowship, Stanford University, School of Medicine, USA

1990 – Woods Hole Summer Student Tuition Scholarship, Marine Biology Laboratories, USA

1985  –  President’s List, Ramapo College, USA

1985 –   Women’s Leader Award, Ramapo College, USA

1985 – Fellowship in Biomedical Research, New York Medical College, USA

1982-1985 – Dean’s List, Ramapo College, USA

Selected publications