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Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Biology, “Tor Vergata” University of Rome, Via della Ricerca Scientifica, 00133, Rome, Italy

    Daniela De Zio, Salvatore Rizza & Giuseppe Filomeni

  2. Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Daniela De Zio, Salvatore Rizza, Søs Grønbæk Mathiassen & Giuseppe Filomeni

  3. Laboratory of Skeletal Muscle Development and Metabolism, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy

    Francesca Molinari, Lucia Gatta, Giuseppe Rosano & Elisabetta Ferraro

  4. Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Rome, Italy

    Maria Teresa Ciotti

  5. Institute of Neurobiology and Molecular Medicine, National Research Council (CNR), Rome, Italy

    Anna Maria Salvatore

  6. Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), via Morego 30, 16163, Genoa, Italy

    Andrzej W. Cwetsch

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  1. Daniela De Zio
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Correspondence to Elisabetta Ferraro.

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De Zio, D., Molinari, F., Rizza, S. et al. Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth. Cell. Mol. Life Sci. 72, 4173–4191 (2015). https://doi.org/10.1007/s00018-015-1927-x

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