Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium
The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.
Vyšlo v časopise:
Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002638
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002638
Souhrn
The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.
Zdroje
1. HorwoodLJMogridgeNDarlowBA 1998 Cognitive, educational, and behavioural outcomes at 7 to 8 years in a national very low birthweight cohort. Arch Dis Child Fetal Neonatal Ed 79 F12 20
2. BassJLCorwinMGozalDMooreCNishidaH 2004 The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics 114 805 16
3. BarrettRDBennetLDavidsonJDeanJMGeorgeS 2007 Destruction and reconstruction: hypoxia and the developing brain. Birth Defects Res C Embryo Today 81 163 76
4. SaigalSDoyleLW 2008 An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 371 261 9
5. MathiasenRHansenBMFormanJLKessingLVGreisenG 2011 The risk of psychiatric disorders in individuals born prematurely in Denmark from 1974 to 1996. Acta Paediatr 100 691 9
6. FanaroffAAStollBJWrightLLCarloWAEhrenkranzRA 2007 Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196 e1 8
7. HintzSRKendrickDEWilson-CostelloDEDasABellEF 2011 Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at <25 Weeks' Gestational Age. Pediatrics 127 62 70
8. MathewsTJMiniñoAMOstermanMJStrobinoDMGuyerB 2011 Annual summary of vital statistics: 2008. Pediatrics 127 146 57
9. GozzoYVohrBLacadieCHampsonMKatzKH 2009 Alterations in neural connectivity in preterm children at school age. Neuroimage 48 458 63
10. MullenKMVohrBRKatzKHSchneiderKCLacadieC 2011 Preterm birth results in alterations in neural connectivity at age 16 years. Neuroimage 54 2563 70
11. HuangHZhangJWakanaSZhangWRenT 2006 White and gray matter development in human fetal, newborn and pediatric brains. Neuroimage 33 27 38
12. HuntCECorwinMJWeese-MayerDEDavidson WardSLRamanathanR 2011 Longitudinal Assessment of Hemoglobin Oxygen Saturation in Preterm and Term Infants in the First Six Months of Life. J Pediatr 159 377 83
13. PocockRHobertO 2008 Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans. Nat Neurosci 11 894 900
14. DoyleLWCrowtherCAMiddletonPMarretSRouseD 2009 Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev Jan 21 CD004661
15. PadillaPARothMB 2001 Oxygen deprivation causes suspended animation in the zebrafish embryo. Proc Natl Acad Sci U S A 98 7331 5
16. MendelsohnBAKassebaumBLGitlinJD 2008 The zebrafish embryo as a dynamic model of anoxia tolerance. Dev Dyn 237 1780 8
17. BonkowskyJLWangXFujimotoELeeJEChienCB 2008 Domain-specific regulation of foxP2 CNS expression by lef1. BMC Dev Biol 8 103
18. WilsonSWRossLSParrettTEasterSSJr 1990 The development of a simple scaffold of axon tracts in the brain of the embryonic zebrafish, Brachydanio rerio. Development 108 121 45
19. SemenzaGL 1999 Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15 551 78
20. MajmundarAJWongWJSimonMC 2010 Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40 294 309
21. PopoviciRMLuMBhatiaSFaessenGHGiacciaAJ 2001 Hypoxia regulates insulin-like growth factor-binding protein 1 in human fetal hepatocytes in primary culture: suggestive molecular mechanisms for in utero fetal growth restriction caused by uteroplacental insufficiency. J Clin Endocrinol Metab 86 2653 9
22. KajimuraSAidaKDuanC 2005 Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation. Proc Natl Acad Sci U S A 102 1240 5
23. KajimuraSAidaKDuanC 2006 Understanding hypoxia-induced gene expression in early development: in vitro and in vivo analysis of hypoxia-inducible factor 1-regulated zebra fish insulin-like growth factor binding protein 1 gene expression. Mol Cell Biol 26 1142 55
24. WattsKDMcColleySA 2011 Elevated vascular endothelial growth factor is correlated with elevated erythropoietin in stable, young cystic fibrosis patients. Pediatr Pulmonol 46 683 7
25. van RooijenEVoestEELogisterIKorvingJSchwerteT 2009 Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood 113 6449 60
26. LeeKLeeJHBoovanahalliSKJinYLeeM 2007 (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors. J Med Chem 50 1675 84
27. ScheerNCampos-OrtegaJA 1999 Use of the Gal4-UAS technique for targeted gene expression in the zebrafish. Mech Dev 80 153 8
28. KellyBDHackettSFHirotaKOshimaYCaiZ 2003 Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93 1074 81
29. ProvostERheeJLeachSD 2007 Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos. Genesis 45 625 9
30. FujimotoEStevensonTJChienCBBonkowskyJL 2011 Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification. Dev Biol 352 393 404
31. ImondiRKaprielianZ 2001 Commissural axon pathfinding on the contralateral side of the floor plate: a role for B-class ephrins in specifying the dorsoventral position of longitudinally projecting commissural axons. Development 128 4859 71
32. KadisonSRMäkinenTKleinRHenkemeyerMKaprielianZ 2006 EphB receptors and ephrin-B3 regulate axon guidance at the ventral midline of the embryonic mouse spinal cord. J Neurosci 26 8909 14
33. CookeJEKempHAMoensCB 2005 EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Curr Biol 15 536 42
34. SatoTHamaokaTAizawaHHosoyaTOkamotoH 2007 Genetic single-cell mosaic analysis implicates ephrinB2 reverse signaling in projections from the posterior tectum to the hindbrain in zebrafish. J Neurosci 27 5271 9
35. PasqualeEB 2008 Eph-ephrin bidirectional signaling in physiology and disease. Cell 133 38 52
36. GilmanSRIossifovILevyDRonemusMWiglerM 2011 Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70 898 907
37. BashawGJKleinR 2010 Signaling from axon guidance receptors. Cold Spring Harb Perspect Biol 2 a001941
38. AltunZFHallDH 2011 Nervous system, general description. WormAtlas doi:10.3908/wormatlas.1.18
39. BoulinTPocockRHobertO 2006 A novel Eph receptor-interacting IgSF protein provides C. elegans motoneurons with midline guidepost function. Curr Biol 16 1871 83
40. SethACulverwellJWalkowiczMToroSRickJM 2006 belladonna/(Ihx2) is required for neural patterning and midline axon guidance in the zebrafish forebrain. Development 133 725 35
41. MohamedAMChin-SangID 2006 Characterization of loss-of-function and gain-of-function Eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration. Dev Biol 290 164 76
42. MendesSWHenkemeyerMLieblDJ 2006 Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain. J Neurosci 26 882 92
43. BushJOSorianoP 2009 Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23 1586 99
44. GathwalaGKheraASinghJBalharaB 2010 Magnesium for neuroprotection in birth asphyxia. J Pediatr Neurosci 5 102 4
45. VangbergTRSkranesJDaleAMMartinussenMBrubakkAM 2006 Changes in white matter diffusion anisotropy in adolescents born prematurely. Neuroimage 32 1538 48
46. ConstableRTMentLRVohrBRKeslerSRFulbrightRK 2008 Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects. Pediatrics 121 306 16
47. NagyZWesterbergHSkareSAnderssonJLLiljaA 2003 Preterm children have disturbances of white matter at 11 years of age as shown by diffusion tensor imaging. Pediatr Res 54 672 9
48. CaldúXNarberhausAJunquéCGiménezMVendrellP 2006 Corpus callosum size and neuropsychologic impairment in adolescents who were born preterm. J Child Neurol 21 406 10
49. SkranesJVangbergTRKulsengSIndredavikMSEvensenKA 2007 Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain 130 654 66
50. MinshewNJWilliamsDL 2007 The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol 64 945 50
51. CurristinSMCaoAStewartWBZhangHMadriJA 2002 Disrupted synaptic development in the hypoxic newborn brain. Proc Natl Acad Sci USA 99 15729 34
52. KimmelCBBallardWWKimmelSRUllmannBSchillingTF 1995 Stages of embryonic development of the zebrafish. Dev Dyn 203 253 310
53. BonkowskyJLChienCB 2005 Molecular cloning and developmental expression of foxP2 in zebrafish. Dev Dyn 234 740 6
54. KwanKMFujimotoEGrabherCMangumBDHardyME 2007 The Tol2kit: A multisite gateway-based construction kit for Tol2 transposon transgenesis constructs. Dev Dyn 236 3088 3099
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 4
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- A Coordinated Interdependent Protein Circuitry Stabilizes the Kinetochore Ensemble to Protect CENP-A in the Human Pathogenic Yeast
- Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
- Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal Models
- Formation of Rigid, Non-Flight Forewings (Elytra) of a Beetle Requires Two Major Cuticular Proteins