title: FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation.
abstract: The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Abdulrzag F
authors.initials: AF
authors.lastname: Ahmed
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.|Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Charles E
authors.initials: CE
authors.lastname: de Bock
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.|Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW, 2298, Australia.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Lincz
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Jay
authors.initials: J
authors.lastname: Pundavela
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Ihssane
authors.initials: I
authors.lastname: Zouikr
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, NSW, 2308, Australia.
authors.forename: Estelle
authors.initials: E
authors.lastname: Sontag
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia.|Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
authors.affiliation: Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia. Rick.Thorne@newcastle.edu.au.|School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, 2258, Australia. Rick.Thorne@newcastle.edu.au.
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
mesh_terms: D021581:Active Transport, Cell Nucleus; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cadherin; Differentiation; FAT1 cadherin; Hippo pathway; Neurite outgrowth; Neuronal differentiation; SMAD transcription factor; TAZ; TGFβ signalling