caa a22 4500 60617706X CHVBK 20210128100750.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00018-015-1955-6 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1955-6 FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation [Elektronische Daten] [Abdulrzag Ahmed, Charles de Bock, Lisa Lincz, Jay Pundavela, Ihssane Zouikr, Estelle Sontag, Hubert Hondermarck, Rick Thorne] 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. Springer Basel, 2015 FAT1 cadherin nationallicence Cadherin nationallicence Differentiation nationallicence Hippo pathway nationallicence Neurite outgrowth nationallicence Neuronal differentiation nationallicence SMAD transcription factor nationallicence TAZ nationallicence TGFβ signalling nationallicence CTGF : Connective tissue growth factor nationallicence NC : Negative control nationallicence NSC : Neuronal stem cell nationallicence NTS : Non-targeting sequence nationallicence qPCR : Quantitative real time PCR nationallicence RA : Retinoic acid nationallicence TEAD : Transcriptional enhancer activator (TEA) domain nationallicence TPA : 12-O-tetradecanoyl-phorbol-13-acetate nationallicence Ahmed Abdulrzag School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut de Bock Charles School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Lincz Lisa School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Pundavela Jay School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Zouikr Ihssane School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Sontag Estelle School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Hondermarck Hubert School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut Thorne Rick Hunter Medical Research Institute, 2305, New Lambton Heights, NSW, Australia aut Cellular and Molecular Life Sciences Springer International Publishing 72/23(2015-12-01), 4653-4669 1420-682X 72:23<4653 2015 72 18 https://doi.org/10.1007/s00018-015-1955-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1955-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ahmed Abdulrzag School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- de Bock Charles School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Lincz Lisa School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Pundavela Jay School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Zouikr Ihssane School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Sontag Estelle School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Hondermarck Hubert School of Biomedical Sciences and Pharmacy, University of Newcastle, 2308, Callaghan, NSW, Australia aut NATIONALLICENCE 700 1- Thorne Rick Hunter Medical Research Institute, 2305, New Lambton Heights, NSW, Australia aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer International Publishing 72/23(2015-12-01), 4653-4669 1420-682X 72:23<4653 2015 72 18