title: Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth.
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.
authors.affiliation: Department of Biology, "Tor Vergata" University of Rome, Via della Ricerca Scientifica, 00133, Rome, Italy.|Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.affiliation: Laboratory of Skeletal Muscle Development and Metabolism, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.affiliation: Department of Biology, "Tor Vergata" University of Rome, Via della Ricerca Scientifica, 00133, Rome, Italy.|Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Rizza
authors.affiliation: Laboratory of Skeletal Muscle Development and Metabolism, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gatta
authors.affiliation: Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: Institute of Neurobiology and Molecular Medicine, National Research Council (CNR), Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Salvatore
authors.affiliation: Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
authors.forename: Søs Grønbæk
authors.initials: SG
authors.lastname: Mathiassen
authors.affiliation: Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), via Morego 30, 16163, Genoa, Italy.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Cwetsch
authors.affiliation: Department of Biology, "Tor Vergata" University of Rome, Via della Ricerca Scientifica, 00133, Rome, Italy.|Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
authors.affiliation: Laboratory of Skeletal Muscle Development and Metabolism, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rosano
authors.affiliation: Laboratory of Skeletal Muscle Development and Metabolism, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy. elisabetta.ferraro@sanraffaele.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferraro
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics* / Q000378:metabolism*; D001369:Axons / Q000473:pathology* / Q000502:physiology; D002454:Cell Differentiation; D018385:Centrosome / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology / Q000473:pathology*; D000076122:Disks Large Homolog 4 Protein; D018507:Gene Expression Regulation, Developmental; D006056:Golgi Apparatus / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D051528:Guanylate Kinases
keywords: Centrosome; Golgi; Mitochondria; NF1; Neuro-rehabilitation; Rab GTPases