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Cellular and Molecular Life Sciences

, Volume 72, Issue 21, pp 4173–4191 | Cite as

Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth

  • Daniela De Zio
  • Francesca Molinari
  • Salvatore Rizza
  • Lucia Gatta
  • Maria Teresa Ciotti
  • Anna Maria Salvatore
  • Søs Grønbæk Mathiassen
  • Andrzej W. Cwetsch
  • Giuseppe Filomeni
  • Giuseppe Rosano
  • Elisabetta FerraroEmail author
Research Article

Abstract

The establishment of neuronal polarity and axonal outgrowth are key processes affecting neuronal migration and synapse formation, their impairment likely leading to cognitive deficits. Here we have found that the apoptotic protease activating factor 1 (Apaf1), apart from its canonical role in apoptosis, plays an additional function in cortical neurons, where its deficiency specifically impairs axonal growth. Given the central role played by centrosomes and microtubules in the polarized extension of the axon, our data suggest that Apaf1-deletion affects axonal outgrowth through an impairment of centrosome organization. In line with this, centrosomal protein expression, as well as their centrosomal localization proved to be altered upon Apaf1-deletion. Strikingly, we also found that Apaf1-loss affects trans-Golgi components and leads to a robust activation of AMP-dependent protein kinase (AMPK), this confirming the stressful conditions induced by Apaf1-deficiency. Since AMPK hyper-phosphorylation is known to impair a proper axon elongation, our finding contributes to explain the effect of Apaf1-deficiency on axogenesis. We also discovered that the signaling pathways mediating axonal growth and involving glycogen synthase kinase-3β, liver kinase B1, and collapsing-response mediator protein-2 are altered in Apaf1-KO neurons. Overall, our results reveal a novel non-apoptotic role for Apaf1 in axonal outgrowth, suggesting that the neuronal phenotype due to Apaf1-deletion could not only be fully ascribed to apoptosis inhibition, but might also be the result of defects in axogenesis. The discovery of new molecules involved in axonal elongation has a clinical relevance since it might help to explain neurological abnormalities occurring during early brain development.

Keywords

Centrosome Golgi Rab GTPases NF1 Mitochondria Neuro-rehabilitation 

Abbreviations

ACC

Acetyl-CoA carboxylase

AMPK

AMP-dependent protein kinase

Apaf1

Apoptotic protease activating factor 1

CRMP2

Collapsing-response mediator protein-2

DIV

Day in vitro

Diva

Death inducer binding to vBcl2 and Apaf1

ETNA

Embryonic telencephalic naïve Apaf1

Gap43

Growth associated protein 43

GDI

GDP dissociation inhibitor

GM130

cis-Golgi marker

GSK3β

Glycogen synthase kinase-3β

HCA66

Hepatocellular carcinoma-associated antigen 66

I-MEFs

Immortalized mouse embryonic fibroblasts

LKB1

Liver kinase B1

MAP2

Microtubule-associated protein 2

MAPs

Microtubule-associated proteins

MARK

Microtubule affinity-regulating kinase

NEDD1

Neural precursor cell expressed developmentally down-regulated protein 1

NF1

Neurofibromatosis type I

PCN

Primary cortical neurons

PSD95

Postsynaptic density protein 95

Rab8

Ras-related in brain 8

Rab10

Ras-related in brain 10

SMI312

Pan-axonal neurofilament marker

Tau

Tau protein

Tom20

Translocase of outer membrane 20

Tubb3

Tubulin, beta 3 class III

Notes

Acknowledgments

This work was supported by the Italian Ministry of Health (RF-2010-2318508 to E Ferraro, Institutional research–Ricerca corrente and GR-2008-1138121 to G Filomeni). We wish to thank MW Bennett for the valuable editorial work, V Frezza for technical support, and M Canossa, L. Cancedda, E. Santonico, N. Canu, L.Vitiello and M Racaniello for helpful discussions. We are also grateful to A Merdes (CNRS-Pierrre-Fabre, Toulouse, France) for kindly providing the HCA66 antibody.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

18_2015_1927_MOESM1_ESM.pdf (2.3 mb)
Supplementary material 1 (PDF 2330 kb)
18_2015_1927_MOESM2_ESM.pdf (210 kb)
Supplementary material 2 (PDF 209 kb)
18_2015_1927_MOESM3_ESM.pdf (1.4 mb)
Supplementary material 3 (PDF 1410 kb)
18_2015_1927_MOESM4_ESM.pdf (5.2 mb)
Supplementary material 4 (PDF 5357 kb)

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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Daniela De Zio
    • 1
    • 2
  • Francesca Molinari
    • 3
  • Salvatore Rizza
    • 1
    • 2
  • Lucia Gatta
    • 3
  • Maria Teresa Ciotti
    • 4
  • Anna Maria Salvatore
    • 5
  • Søs Grønbæk Mathiassen
    • 2
  • Andrzej W. Cwetsch
    • 6
  • Giuseppe Filomeni
    • 1
    • 2
  • Giuseppe Rosano
    • 3
  • Elisabetta Ferraro
    • 3
    Email author
  1. 1.Department of Biology“Tor Vergata” University of RomeRomeItaly
  2. 2.Cell Stress and Survival UnitDanish Cancer Society Research CenterCopenhagenDenmark
  3. 3.Laboratory of Skeletal Muscle Development and MetabolismIRCCS San Raffaele PisanaRomeItaly
  4. 4.Institute of Cell Biology and Neurobiology (IBCN)National Research Council (CNR)RomeItaly
  5. 5.Institute of Neurobiology and Molecular MedicineNational Research Council (CNR)RomeItaly
  6. 6.Department of Neuroscience and Brain TechnologiesItalian Institute of Technology (IIT)GenoaItaly

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