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Progenitor Cell Populations in the Postnatal Pons

  • Author(s): Lindquist, Robert Adam
  • Advisor(s): Alvarez-Buylla, Arturo
  • Rowitch, David H
  • et al.
Abstract

The pons has key sensorimotor and autonomic functions; serves as an important relay of motor information between neocortex and cerebellum; and is the site of the deadliest childhood brain tumor, Diffuse Intrinsic Pontine Glioma (DIPG), which may originate in development. Despite the importance of the pons, little is known about its postnatal development. MRI analysis revealed that the human pons grows six-fold postnatally, and histologic analysis revealed that the mouse pons grows four-fold postnatally, with most rapid growth rates during infancy in both species. Immunohistochemistry in postmortem pediatric pons tissue revealed that proliferation in human pons was greatest at birth and declined to near zero by 18 months, remaining low through the remainder of childhood; proliferation in mouse pons was greatest at postnatal day 4 (P4) and declined 10-fold by weaning age, remaining low through adulthood. In both humans and mice, the peak age of proliferation coincided with the peak period of growth. In mouse pons, proliferative progenitors were found in three anatomical compartments: ventricular, midline, and parenchymal. Cre recombinase-based fate-mapping of midline and ventricular populations showed that they gave rise to few cells outside their respective anatomical compartments, implying that most cell addition occurs by parenchymal proliferation. In both human and mouse, growth and proliferation were greater in the ventral pons (basis pontis) than dorsal pons (tegmentum), and a majority of proliferative cells expressed Olig2. In mice, co-staining of BrdU with Sox10 and NG2:DsRed identified most parenchymal proliferative cells as committed oligodendrocyte precursors, while a minority of BrdU+ cells were ALDH1L1:GFP+ astrocytes. Most proliferative progenitors expressed both Olig2 and Sox2, with a BrdU+Olig2+Sox2- population peaking later, at the onset of myelination. Sox2CreER fate-mapping revealed that postnatal Sox2+ progenitors gave rise to more than 90% of adult pons oligodendrocytes, contributing to a 10-18 fold postnatal expansion of the pontine oligodendroglial population. Together, these studies provide the first longitudinal studies of growth, proliferation, and gliogenesis in the postnatal pons, identifying evolutionarily conserved populations of postnatal progenitor cells that drive pontine growth, may contribute to the postnatal acquisition of motor coordination, and represent candidate cells of origin for DIPG.

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