title: Systemic hypoxia differentially affects neurogenesis during early mouse brain maturation.
abstract: BACKGROUND
  Cerebral tissue oxygen level modifies crucial processes of neurogenesis, glial and neuronal development during physiological and hypoxic conditions. Whether hypoxia-sensitive factors such as doublecortin (DCX) and hypoxia-inducible transcription factor (HIF)-regulated CXCR4 and SDF-1 modify and activate adaptation to hypoxia in developing brain is not well understood. Present study investigated maturational regulation of oxygen-sensitive developmental genes and proteins in developing mouse brain in relation to the degree of hypoxia.
  
  
  METHODS
  Physiological expression of HIF-1, CXCR4, SDF-1 and DCX were analyzed in the brain of C57/BL6 mice (P0-P60). In addition, mice (P0, P7) were exposed to normoxia, acute (8% O(2), 6 h) or chronic hypoxia (10% O(2), 7 d) followed by reoxygenation. Gene expression was analyzed by quantitative PCR, proteins were quantified by Western blot analysis and immunohistochemistry.
  
  
  RESULTS
  Cerebral HIF-1α protein, CXCR4 and DCX mRNA levels showed maturational stage-related peak levels at P0/P1, whereas SDF-1 mRNA levels were highest at P17. CXCR4 and SDF-1 mRNA levels were not altered in response to hypoxia. Whereas DCX mRNA levels significantly increased during acute hypoxia, down-regulation of DCX transcripts was found in response to chronic hypoxia compared to controls, and these changes were related to specifically vulnerable brain regions.
  
  
  CONCLUSIONS
  Maturational stage-related dynamic changes of HIF-1α, CXCR4, SDF-1 and DCX may reflect involvement of hypoxia-regulated systems in important developmental regulatory processes of the developing brain. Extending the knowledge of differential effects of hypoxia on neurogenesis and dynamic regulatory networks present data provide a basis for future research on gestational age-specific neuroprotective options.
authors.affiliation: Department of Pediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schneider
authors.forename: Gudrun
authors.initials: G
authors.lastname: Krischke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D002908:Chronic Disease; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D002534:Hypoxia, Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D019718:Receptors, CXCR4