Document Type



Medicine and Health Sciences


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 non-cycling Sox2+ radial glial cells as well as 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 employed a rabbit model and compared preterm (E29, 3 days old) and term pups (E32, <2h age) at an equivalent post-conceptional age. Glutamatergic neurogenesis was suppressed in preterm rabbits, as indicated by reduced number of Tbr2+ intermediate progenitors and 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, Neurogenin-1 and -2, were higher in preterm rabbit pups compared to 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.


J Neurosci. Author manuscript; available in PMC 2013 July 15. Published in final edited form as: J Neurosci. 2013 January 9; 33(2): 411–423. doi: 10.1523/JNEUROSCI.4445-12.2013 PMCID: PMC3711635 NIHMSID: NIHMS431508