title: Oxygen flux reduces Cux1 positive neurons and cortical growth in a gestational rodent model of growth restriction.
abstract: BACKGROUND
  The mammalian cerebral cortex forms in an inside-out manner, establishing deep cortical layers before superficial layers and is regulated by transcription factors which influence cell differentiation. Preterm birth interrupts the trajectory of normal neurodevelopment and adverse perinatal exposures have been implicated in cortical injury. We hypothesise that growth restriction (GR) and fluctuating hyperoxia (ΔO2) impair cortical laminar development.
  
  
  METHODS
  Sprague-Dawley rats received 18% (non-restricted, NR) or 9% (growth restricted, GR) protein diet from E15-P7. Litters were reared in air or fluctuating hyperoxia (circa 10kPa) from P0 to P7. Cortical laminae were stained and measured. Neuronal subtypes were quantified using immunofluorescence for subtype-specific transcription factors (Satb2, Cux1, Ctip2, Tbr1).
  
  
  RESULTS
  ΔO2did not affect brain weight at P7 but reduced cortical thickness in both NR (p<0.05) and GR groups (p<0.001). ΔO2resulted in superficial cortical thinning in both groups and in the deep layers of GR pups (p<0.001). Cell density was preserved. ΔO2did not affect proportions of callosal, corticothalamic and corticospinal neurons but resulted in a reduction of neurons expressing Cux1 (p<0.01) implicated in dendritic branching and synapse formation.
  
  
  CONCLUSIONS
  Postnatal ΔO2, a modifiable factor in neonatal care, impairs cortical development in a rodent model with preferential disadvantage to superficial neurons.
authors.affiliation: Jennifer Brown Research Laboratory, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK. Electronic address: elainefletcher2@nhs.net.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fletcher
authors.affiliation: Jennifer Brown Research Laboratory, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Wade
authors.affiliation: Centre of Integrative Physiology, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh, Scotland, EH8 9XD, UK.
authors.forename: Petrina A
authors.initials: PA
authors.lastname: Georgala
authors.affiliation: Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.
authors.forename: Trudi L
authors.initials: TL
authors.lastname: Gillespie
authors.affiliation: Centre of Integrative Physiology, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh, Scotland, EH8 9XD, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.affiliation: Jennifer Brown Research Laboratory, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pilley
authors.affiliation: Jennifer Brown Research Laboratory, Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.
authors.forename: Julie-Clare
authors.initials: JC
authors.lastname: Becher
mesh_terms: D000818:Animals; D001835:Body Weight; D002452:Cell Count; D002540:Cerebral Cortex / Q000254:growth & development* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003712:Dendrites; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000473:pathology*; D018496:Hyperoxia / Q000473:pathology; D009044:Motor Cortex / Q000166:cytology / Q000254:growth & development; D009474:Neurons / Q000473:pathology*; D009929:Organ Size; D010101:Oxygen Consumption; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C088424:Cux1 protein, rat; D004268:DNA-Binding Proteins; D014157:Transcription Factors
keywords: CUX1 protein; Cerebral cortex; Cortical lamination; Fetal growth retardation; Hyperoxia