Cellular and Molecular Life Sciences

, Volume 72, Issue 23, pp 4653–4669 | Cite as

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

  • Abdulrzag F. Ahmed
  • Charles E. de Bock
  • Lisa F. Lincz
  • Jay Pundavela
  • Ihssane Zouikr
  • Estelle Sontag
  • Hubert Hondermarck
  • Rick F. Thorne
Research Article

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.

Keywords

FAT1 cadherin Cadherin Differentiation Hippo pathway Neurite outgrowth Neuronal differentiation SMAD transcription factor TAZ TGFβ signalling 

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

Supplementary material

18_2015_1955_MOESM1_ESM.pdf (2.1 mb)
Supplementary material 1 (PDF 2151 kb)

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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Abdulrzag F. Ahmed
    • 1
    • 2
  • Charles E. de Bock
    • 1
    • 2
    • 6
  • Lisa F. Lincz
    • 1
    • 2
    • 3
  • Jay Pundavela
    • 1
    • 2
  • Ihssane Zouikr
    • 1
    • 2
  • Estelle Sontag
    • 1
    • 4
  • Hubert Hondermarck
    • 1
    • 2
  • Rick F. Thorne
    • 2
    • 5
  1. 1.School of Biomedical Sciences and PharmacyUniversity of NewcastleCallaghanAustralia
  2. 2.Hunter Medical Research InstituteNew Lambton HeightsAustralia
  3. 3.Hunter Haematology Research GroupCalvary Mater Newcastle HospitalWaratahAustralia
  4. 4.Priority Research Centre for Translational Neuroscience and Mental HealthUniversity of NewcastleCallaghanAustralia
  5. 5.School of Environmental and Life SciencesUniversity of NewcastleOurimbahAustralia
  6. 6.Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of DiseaseVIBLeuvenBelgium

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