摘要
The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.
The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.
引文
Alberghina L,Colangelo AM(2006)The modular systems biology approach to investigate the control of apoptosis in Alzheimer’s disease neurodegeneration.BMC Neurosci 7 Suppl 1:S2.
Ashrafi G,Schwarz TL(2013)The pathways of mitophagy for quality control and clearance of mitochondria.Cell Death Differ 20:31-42.
Bakker BM,Michels PA,Opperdoes FR,Westerhoff HV(1999)What controls glycolysis in bloodstream form Trypanosoma brucei?J Biol Chem274:14551-14559.
Bianco MR,Berbenni M,Amara F,Viggiani S,Fragni M,Galimberti V,Colombo D,Cirillo G,Papa M,Alberghina L,Colangelo AM(2011)Crosstalk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells.J Neurosci Res 89:1302-1315.
Brady NR,Hamacher-Brady A,Westerhoff HV,Gottlieb RA(2006)A wave of reactive oxygen species(ROS)-induced ROS release in a sea of excitable mitochondria.Antioxid Redox Signal 8:1651-1665.
Chao MV(2003)Neurotrophins and their receptors:a convergence point for many signalling pathways.Nature Rev Neurosci 4:299-309.
Cirillo G,Colangelo AM,De Luca C,Savarese L,Barillari MR,Alberghina L,Papa M(2016)Modulation of matrix metalloproteinases activity in the ventral horn of the spinal cord restores neuroglial synaptic homeostasis and neurotrophic support following peripheral nerve injury.PLoS One11:e0152750.
Colangelo AM,Follesa P,Mocchetti I(1998)Differential induction of nerve growth factor and basic fibroblast growth factor mRNA in neonatal and aged rat brain.Brain Res Mol Brain Res 53:218-225.
De Bernardi MA,Rabins SJ,Colangelo AM,Brooker G,Mocchetti I(1996)TrkA mediates the nerve growth factor-induced intracellular calcium accumulation.J Biol Chem 271:6092-6098.
De Luca C,Savarese L,Colangelo AM,Bianco MR,Cirillo G,Alberghina L,Papa M(2016)Astrocytes and microglia-mediated immune response in maladaptive plasticity is differently modulated by NGF in the ventral horn of the spinal cord following peripheral nerve injury.Cell Mol Neurobiol 36:37-46.
Doetsch F,Petreanu L,Caille I,Garcia-Verdugo JM,Alvarez-Buylla A(2002)EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells.Neuron 36:1021-1034.
Dokter M,von Bohlen und Halbach O(2012)Neurogenesis within the adult hippocampus under physiological conditions and in depression.Neural Regen Res 7:552-559.
Ergin V,Erdogan M,Menevse A(2015)Regulation of Shootin1 gene expression involves NGF-induced alternative splicing during neuronal differentiation of PC12 cells.Sci Rep 5:17931.
Eriksson PS,Perfilieva E,Bj?rk-Eriksson T,Alborn AM,Nordborg C,Peterson DA,Gage FH(1998)Neurogenesis in the adult human hippocampus.Nat Med 4:1313-1317.
Faure A,Verret L,Bozon B,El Tannir El Tayara N,Ly M,Kober F,Dhenain M,Rampon C,Delatour B(2011)Impaired neurogenesis,neuronal loss,and brain functional deficits in the APPxPS1-Ki mouse model of Alzheimer’s disease.Neurobiol Aging 32:407-418.
Gage FH(2000)Mammalian neural stem cells.Science 287:1433-1438.
Gallo G(2011)The cytoskeletal and signaling mechanisms of axon collateral branching.Dev Neurobiol 71:201-220.
Gao Z,Ure K,Ables JL,Lagace DC,Nave KA,Goebbels S,Eisch AJ,Hsieh J(2009)Neurod1 is essential for the survival and maturation of adult-born neurons.Nat Neurosci 12:1090-1092.
Griffiths EJ,Rutter GA(2009)Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells.Biochim Biophys Acta 1787:1324-1333.
Groen AK,Wanders RJ,Westerhoff HV,Van der Meer R,Tager JM(1982)Quantification of the contribution of various steps to the control of mitochondrial respiration.J Biol Chem 257:2754-2757.
Haanstra JR,Gerding A,Dolga AM,Sorgdrager FJH,Buist-Homan M,du Toit F,Faber KN,Holzhütter HG,Sz??r B,Matthews KR,Snoep JL,Westerhoff HV,Bakker BM(2017)Targeting pathogen metabolism without collateral damage to the host.Sci Rep 7:40406.
Heinrich R,Rapoport TA(1974)A linear steady-state treatment of enzymatic chains.General properties,control and effector strength.Eur J Biochem42:89-95.
H?glinger GU,Rizk P,Muriel MP,Duyckaerts C,Oertel WH,Caille I,Hirsch EC(2004)Dopamine depletion impairs precursor cell proliferation in Parkinson disease.Nat Neurosci 7:726-735.
Hornberg JJ,Bruggeman FJ,Binder B,Geest CR,de Vaate AJ,Lankelma J,Heinrich R,Westerhoff HV(2005)Principles behind the multifarious control of signal transduction.ERK phosphorylation and kinase/phosphatase control.FEBS J 272:244-58.
Hornberg JJ,Bruggeman FJ,Westerhoff HV,Lankelma J(2006)Cancer:a systems biology disease.Biosystems 83:81-90.
Ihunwo AO,Tembo LH,Dzamalala C(2016)The dynamics of adult neurogenesis in human hippocampus.Neural Regen Res 11:1869-1883.
Kacser H,Burns JA(1973)The control of flux.Symp Soc Exp Biol 27:65-104.
Kempermann G,Kuhn HG,Gage FH(1997)More hippocampal neurons in adult mice living in an enriched environment.Nature 386:493-495.
Knoth R,Singec I,Ditter M,Pantazis G,Capetian P,Meyer RP,Horvat V,Volk B,Kempermann G(2010)Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.PLoS One5:e8809.
Kolodkin A,Simeonidis E,Balling R,Westerhoff HV(2012)Understanding complexity in neurodegenerative diseases:in silico reconstruction of emergence.Front Physiol 3:291.
Kornack DR,Rakic P(1999)Continuation of neurogenesis in the hippocampus of the adult macaque monkey.Proc Natl Acad Sci U S A 96:5768-5773.
Kornack DR,Rakic P(2001)The generation,migration,and differentiation of olfactory neurons in the adult primate brain.Proc Natl Acad Sci U S A98:4752-4757.
Kuhn HG,Dickinson-Anson H,Gage FH(1996)Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation.J Neurosci 16:2027-2033.
Lavado A,Lagutin OV,Chow LM,Baker SJ,Oliver G(2010)Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis.PLoS Biol 8:e1000460.
Lindvall O,Kokaia Z(2015)Neurogenesis following stroke affecting the adult brain.Cold Spring Harb Perspect Biol 7:a019034.
Mahar I,Bambico FR,Mechawar N,Nobrega JN(2014)Stress,serotonin,and hippocampal neurogenesis in relation to depression and antidepressant effects.Neurosci Biobehav Rev 38:173-192.
Martorana F,Gaglio D,Bianco MR,Aprea F,Virtuoso A,Bonanomi M,Alberghina L,Papa M,Colangelo AM(2018)Differentiation by nerve growth factor(NGF)Involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling.Cell Death Dis 9:391.
Ming GL,Song H(2011)Adult neurogenesis in the mammalian brain:significant answers and significant questions.Neuron 70:687-702.
Munnamalai V,Weaver CJ,Weisheit CE,Venkatraman P,Agim ZS,Quinn MT,Suter DM(2014)Bidirectional interactions between NOX2-type NADPH oxidase and the F-actin cytoskeleton in neuronal growth cones.JNeurochem 130:526-540.
Ng YP,Wu Z,Wise H,Tsim KW,Wong YH,Ip NY(2009)Differential and synergistic effect of nerve growth factor and cAMP on the regulation of early response genes during neuronal differentiation.Neurosignals17:111-120.
Olguín-Albuerne M,Morán J(2015)ROS produced by NOX2 control in vitro development of cerebellar granule neurons development.ASN Neuro7:1759091415578712.
Paik JH,Ding Z,Narurkar R,Ramkissoon S,Muller F,Kamoun WS,Chae SS,Zheng H,Ying H,Mahoney J,Hiller D,Jiang S,Protopopov A,Wong WH,Chin L,Ligon KL,DePinho RA(2009)FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis.Cell Stem Cell 5:540-553.
Pirhaji L,Milani P,Leidl M,Curran T,Avila-Pacheco J,Clish CB,White FM,Saghatelian A,Fraenkel E(2016)Revealing disease-associated pathways by network integration of untargeted metabolomics.Nat Methods13:770-776.
Scardigli R,Capelli P,Vignone D,Brandi R,Ceci M,La Regina F,Piras E,Cintoli S,Berardi N,Capsoni S,Cattaneo A(2014)Neutralization of nerve growth factor impairs proliferation and differentiation of adult neural progenitors in the subventricular zone.Stem Cells 32:2516-2528.
Shan X,Chi L,Bishop M,Luo C,Lien L,Zhang Z,Liu R(2006)Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease-like mice.Stem Cells 24:1280-1287.
Shruster A,Ben-Zur T,Melamed E,Offen D(2012)Wnt signaling enhances neurogenesis and improves neurological function after focal ischemic injury.PLoS One 7:e40843.
Sierra-Fonseca JA,Najera O,Martinez-Jurado J,Walker EM,Varela-Ramirez A,Khan AM,Miranda M,Lamango NS,Roychowdhury S(2014)Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gβγ-microtubule interaction.BMC Neurosci 15:132.
Snoep JL,van der Weijden CC,Andersen HW,Westerhoff HV,Jensen PR(2002)DNA supercoiling in Escherichia coli in under tight and subtle homeostatic control,involving gene-expression and metabolic regulation of both toposiomerase 1 and DNA gyrase.Eur J Biochem 269:1662-1669.
Sorrells SF,Paredes MF,Cebrian-Silla A,Sandoval K,Qi D,Kelley KW,James D,Mayer S,Chang J,Auguste KI,Chang EF,Gutierrez AJ,Kriegstein AR,Mathern GW,Oldham MC,Huang EJ,Garcia-Verdugo JM,Yang Z,Alvarez-Buylla A(2018)Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.Nature 555:377-381.
Spaccapelo L,Galantucci M,Neri L,Contri M,Pizzala R,D’Amico R,Ottani A,Sandrini M,Zaffe D,Giuliani D,Guarini S(2013)Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia.Eur J Pharmacol707:78-86.
Spillane M,Ketschek A,Merianda TT,Twiss JL,Gallo G(2013)Mitochondria Coordinate Sites of Axon Branching through Localized Intra-Axonal Protein Synthesis.Cell Rep 5:1564-1575.
Suh H,Consiglio A,Ray J,Sawai T,D’Amour KA and Gage FH(2007)In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+neural stem cells in the adult hippocampus.Cell Stem Cell 1:515-528.
Suzukawa K,Miura K,Mitsushita J,Resau J,Hirose K,Crystal R,Kamata T(2000)Nerve growth factor-induced neuronal differentiation requires generation of Rac1-regulated reactive oxygen species.J Biol Chem275:13175-13178.
Taupin P,Gage FH(2002)Adult neurogenesis and neural stem cells of the central nervous system in mammals.J Neurosci Res 69:745-749.
van Praag H,Schinder AF,Christie BR,Toni N,Palmer TD,Gage FH(2002)Functional neurogenesis in the adult hippocampus.Nature 415:1030-1034.
Vieira HL,Alves PM,Vercelli A(2011)Modulation of neuronal stem cell differentiation by hypoxia and reactive oxygen species.Prog Neurobiol93:444-455.
Waki A,Yano R,Yoshimoto M,Sadato N,Yonekura Y,Fujibayashi Y(2001)Dynamic changes in glucose metabolism accompanying the expression of the neural phenotype after differentiation in PC12 cells.Brain Res 894:88-94.
Westermann B(2010)Mitochondrial Fusion and Fission in Cell Life and Death.Nat Rev Mol Cell Biol 11:872-884.
Wirths O(2017)Altered neurogenesis in mouse models of Alzheimer disease.Neurogenesis 4:e1327002.
Wright Muelas M,Ortega F,Breitling R,Bendtsen C,Westerhoff HV(2018)Rational cell culture optimization enhances experimental reproducibility in cancer cells.Sci Rep 8:3029.
Yazdankhah M,Farioli-Vecchioli S,Tonchev AB,Stoykova A,Cecconi F(2014)The autophagy regulators Ambra1 and Beclin 1 are required for adult neurogenesis in the brain subventricular zone.Cell Death Dis5:e1403.
Yoshimi K,Ren YR,Seki T,Yamada M,Ooizumi H,Onodera M,Saito Y,Murayama S,Okano H,Mizuno Y,Mochizuki H(2005)Possibility for neurogenesis in substantia nigra of parkinsonian brain.Ann Neurol58:31-40.
Zhao M,Momma S,Delfani K,Carlen M,Cassidy RM,Johansson CB,Brismar H,Shupliakov O,Frisen J,Janson AM(2003)Evidence for neurogenesis in the adult mammalian substantia nigra.Proc Natl Acad Sci U S A100:7925-7930.
Zhao C,Deng W,Gage FH(2008)Mechanisms and functional implications of adult neurogenesis.Cell 132:645-660.
Zheng X,Boyer L,Jin M,Mertens J,Kim Y,Ma L,Ma L,Hamm M,Gage FH,Hunter T(2016)Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.eLife 5:e13374.