title: Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth.
abstract: Premature infants exhibit neurodevelopmental delay and reduced growth of the cerebral cortex. However, the underlying mechanisms have remained elusive. Therefore, we hypothesized that neurogenesis in the ventricular and subventricular zones of the cerebral cortex would continue in the third trimester of pregnancy and that preterm birth would suppress neurogenesis. To test our hypotheses, we evaluated autopsy materials from human fetuses and preterm infants of 16-35 gestational weeks (gw). We noted that both cycling and noncycling Sox2(+) radial glial cells and Tbr2(+) intermediate progenitors were abundant in human preterm infants until 28 gw. However, their densities consistently decreased from 16 through 28 gw. To determine the effect of premature birth on neurogenesis, we used a rabbit model and compared preterm [embryonic day 29 (E29), 3 d old] and term (E32, <2 h old) pups at an equivalent postconceptional age. Glutamatergic neurogenesis was suppressed in preterm rabbits, as indicated by the reduced number of Tbr2(+) intermediate progenitors and the increased number of Sox2(+) radial glia. Additionally, hypoxia-inducible factor-1α, vascular endothelial growth factor, and erythropoietin were higher in term than preterm pups, reflecting the hypoxic intrauterine environment of just-born term pups. Proneural genes, including Pax6 and Neurogenin-1 and -2, were higher in preterm rabbit pups compared with term pups. Importantly, neurogenesis and associated factors were restored in preterm pups by treatment with dimethyloxallyl glycine, a hypoxia mimetic agent. Hence, glutamatergic neurogenesis continues in the premature infants, preterm birth suppresses neurogenesis, and hypoxia-mimetic agents might restore neurogenesis, enhance cortical growth, and improve neurodevelopmental outcome of premature infants.
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Malik
authors.forename: Govindaiah
authors.initials: G
authors.lastname: Vinukonda
authors.forename: Linnea R
authors.initials: LR
authors.lastname: Vose
authors.forename: Daniel
authors.initials: D
authors.lastname: Diamond
authors.forename: Bala B R
authors.initials: BB
authors.lastname: Bhimavarapu
authors.forename: Furong
authors.initials: F
authors.lastname: Hu
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Zia
authors.forename: Robert
authors.initials: R
authors.lastname: Hevner
authors.forename: Nada
authors.initials: N
authors.lastname: Zecevic
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
mesh_terms: D000328:Adult; D000818:Animals; D002452:Cell Count; D002552:Cerebral Ventricles / Q000254:growth & development; D004921:Erythropoietin / Q000502:physiology; D005260:Female; D005865:Gestational Age; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis / Q000502:physiology; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third / Q000502:physiology*; D047928:Premature Birth / Q000503:physiopathology*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D013687:Telencephalon / Q000254:growth & development; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009419:Nerve Tissue Proteins; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D051176:beta Catenin; D004921:Erythropoietin; D005998:Glycine