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FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation

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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.

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Abbreviations

CTGF:

Connective tissue growth factor

NC:

Negative control

NSC:

Neuronal stem cell

NTS:

Non-targeting sequence

qPCR:

Quantitative real time PCR

RA:

Retinoic acid

TEAD:

Transcriptional enhancer activator (TEA) domain

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

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  1. Charles E. de Bock

    Present address: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium

Authors and Affiliations

  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia

    Abdulrzag F. Ahmed, Charles E. de Bock, Lisa F. Lincz, Jay Pundavela, Ihssane Zouikr, Estelle Sontag & Hubert Hondermarck

  2. Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia

    Abdulrzag F. Ahmed, Charles E. de Bock, Lisa F. Lincz, Jay Pundavela, Ihssane Zouikr, Hubert Hondermarck & Rick F. Thorne

  3. Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW, 2298, Australia

    Lisa F. Lincz

  4. Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, NSW, 2308, Australia

    Estelle Sontag

  5. School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, 2258, Australia

    Rick F. Thorne

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  1. Abdulrzag F. Ahmed
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  2. Charles E. de Bock
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  3. Lisa F. Lincz
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  4. Jay Pundavela
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  5. Ihssane Zouikr
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  6. Estelle Sontag
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  7. Hubert Hondermarck
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  8. Rick F. Thorne
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Corresponding author

Correspondence to Rick F. Thorne.

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Ahmed, A.F., de Bock, C.E., Lincz, L.F. et al. FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation. Cell. Mol. Life Sci. 72, 4653–4669 (2015). https://doi.org/10.1007/s00018-015-1955-6

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  • DOI: https://doi.org/10.1007/s00018-015-1955-6

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