Helen McNeill, PhD
Professor and BJC Investigator
Developmental Biology
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Cancer Biology Program
Molecular Genetics and Genomics Program
Research Abstract:
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.
Selected Publications:
Tsatskis Y, Rosenfeld R, Pearson JD, Boswell C, Qu Y, Kim K, Fabian L, Mohammad A, Wang X, Robson MI, Krchma K, Wu J, Gonçalves J, Hodzic D, Wu S, Potter D, Pelletier L, Dunham WH, Gingras AC, Sun Y, Meng J, Godt D, Schedl T, Ciruna B, Choi K, Perry JRB, Bremner R, Schirmer EC, Brill JA, Jurisicova A, McNeill H. The NEMP family supports metazoan fertility and nuclear envelope stiffness. Science Advances. 2020 Aug 28;6(35):eabb4591. doi: 10.1126/sciadv.abb4591.
Brooun M, Klimovich A, Bashkurov M, Pearson BJ, Steele RE, McNeill H. Ancestral roles of atypical cadherins in planar cell polarity. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19310-19320. doi: 10.1073/pnas.1917570117
Fulford AD, McNeill H. Fat/Dachsous family cadherins in cell and tissue organisation. Current Opinions in Cell Biology. 2020 Feb;62:96-103.
Rao-Bhatia A, Zhu M, Yin WC, Coquenlorge S, Zhang X, Woo J, Sun Y, Dean CH, Liu A, Hui CC, Shivdasani RA, McNeill H, Hopyan S, Kim TH. Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development. Developmental Cell. 2020 Mar 9;52(5):647-658.e6.
Betterman KL, Sutton DL, Secker GA, Kazenwadel J, Oszmiana A, Lim L, Miura N, Sorokin L, Hogan BM, Kahn ML, McNeill H, Harvey NL. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. J Clin Invest. 2020 Jun 1;130(6):3315-3328.
Zhang H, Bagherie-Lachidan M, Badouel C, Enderle L, Peidis P, Bremner R, Kuure S, Jain S, McNeill H. FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling. Dev Cell. 2019 48(6):780-792.e4. doi: 10.1016/j.devcel.2019.02.004.
Arbouzova NI, Fulford AD, Zhang H, McNeill H. Fat regulates expression of four-jointed reporters in vivo through a 20 bp element independently of the Hippo pathway. Dev Biol. 2019 Mar 9. pii: S0012-1606(18)30668-7
Lahrouchi N, George A, Ratbi I, Schneider R, Elalaoui SC, Moosa S, Bharti S, Sharma R, Abu-Asab M, Onojafe F, Adadi N, Lodder EM, Laarabi FZ, Lamsyah Y, Elorch H, Chebbar I, Postma AV, Lougaris V, Plebani A, Altmueller J, Kyrieleis H, Meiner V, McNeill H, Bharti K, Lyonnet S, Wollnik B, Henrion-Caude A, Berraho A, Hildebrandt F, Bezzina CR, Brooks BP, Sefiani A. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly. Nat Commun. 2019 Mar 2;10(1):1180.
Chen J, Castelvecchi GD, Li-Villarreal N, Raught B, Krezel AM, McNeill H, Solnica-Krezel L. Atypical Cadherin Dachsous1b Interacts with Ttc28 and Aurora B to Control Microtubule Dynamics in Embryonic Cleavages. Dev Cell. 2018 May 7;45(3):376-391
Wang X, Liu H, Zhu M, Cao C, Xu Z, Tsatskis Y, Lau K, Kuok C, Filleter T, McNeill H, Simmons CA, Hopyan S, Sun Y. Mechanical stability of the cell nucleus - roles played by the cytoskeleton in nuclear deformation and strain recovery. J Cell Sci. 2018 Jul 4;131(13).
Hoshi M, Reginensi A, Joens MS, Fitzpatrick JAJ, McNeill H, Jain S. Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion. J Am Soc Nephrol. 2018 Mar;29(3):775-783
Blair S & McNeill H. Big roles for Fat cadherins.Curr Opin Cell Biol. 2018 Apr;51:73-80
McNeill H, Reginensi A. Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation. (2017) J Am Soc Nephrol, 28, 852-861.
Yeung K, Boija A, Karlsson E, Holmqvist P-H, Tsatskis Y, Nisoli I, Yap D, Lorzadeh A, Moksa M, Hirst M, Aparicio S, Fanto M, Stenberg P, Mannervik M, McNeill H. Atrophin controls developmental signaling pathways via interactions with Trithorax-like. (2017) eLife,Mar 22;6. pii: e23084. doi: 10.1681/ASN.2016060611.
Sing A, Tsatskis Y, Fabian L, Bietenhader M, Stolz T, Rosenfeld R, Brill J, McQuibban GA, McNeill H. The atypical cadherin Fat directly regulates mitochondrial function and metabolic state. (2014) Cell, 158, 1293-1308.
Sopko R, Silva E, Clayton L, Gardano L, Barrios-Rodiles M, Wrana J, Varelas X, Arbouzova NI, Shaw S, Saburi S, Matakatsu H, Blair S, McNeill H. Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. (2009) Current Biology, 19, 1112-7.
Badouel C, Gardano L, Amin N, Garg, A, Le Bahn T, McNeill H. The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. (2009) Developmental Cell, 16, 411-20
Amin N, Khan A, St Johnston D, Tomlinson T, Martin S, Brenman J, McNeill H. LKB1 regulates cell polarity and adherens junction formation in the Drosophila retina. (2009) Proc Natl Acad Sci, 106, 8941-6.
Saburi S, Hester I, Fischer E, Pontoglio M, Eremina V, Gessler M, Quaggin S, Harrison R, Mount R, McNeill H. Loss of Fat4 disrupts PCP signalling and oriented cell division, leading to cystic kidney disease. (2008) Nature Genetics, 40, 1010-5.
Silva E, Tsatskis Y, Gardano L, Tapon N, McNeill H. The tumour suppressor gene fat controls tissue growth upstream of Expanded in the Hippo signalling pathway. (2006) Current Biology, 7, 2081-2089.
Bateman JM, McNeill H. Temporal control of differentiation by the insulin receptor/Tor pathway in Drosophila. (2004) Cell, 119, 87-96.
Fanto M, Clayton L, Meredith J, Hardiman K, Charroux B, Kerridge S, McNeill H. The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. (2003) Development, 130, 763-774.
Last Updated: 2/22/2021 11:59:28 AM