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Labeling proliferating progenitors at P17 revealed increased generation of cortical NeuN ϩ and Tbr1 ϩ excitatory neurons in wild-type mice subjected to hypoxic insult, whereas Fgfr1 cKO failed to mount a cortical neurogenetic response. Hypoxic wild-type mice also demonstrated a twofold increase in cell proliferation in the subventricular zone (SVZ) at P17 and a threefold increase in neurogenesis in the olfactory bulb (OB) at P48, compared with normoxic mice. In contrast, Fgfr1 cKO mice had decreased SVZ cell proliferation and curtailed reactive neurogenesis in the OB. Thus, the activation of FGFR-1 in GFAPϩ cells is required for neuronal recovery after neonatal hypoxic injury, which is attributable in part to enhanced cortical and OB neurogenesis. In contrast, there is incomplete recovery of inhibitory neurons after injury, which may account for persistent behavioral deficits.

To understand the role of specific fibroblast growth factor receptors (FGFRs) in cortical development, we conditionally inactivated Fgfr2 or both Fgfr1 and Fgfr2 [Fgfr2 conditional knock-out (cKO) or double knock-out mice, respectively] in radial glial cells of the dorsal telencephalon. Fgfr1 and Fgfr2 are necessary for the attainment of a normal number of excitatory neurons in the cerebral cortex. The action of FGF receptors appears to be through increasing self-renewal of neuronal precursors within the ventricular zone. Volume measurements, assessments of excitatory neuron number, and areal marker expression suggested that the proper formation of the medial prefrontal cortex (mPFC) depends on the function of Fgfr2, whereas Fgfr1 together with Fgfr2 control excitatory cortical neuron development within the entire cerebral cortex. Fgfr2 cKO mice had fewer and smaller glutamate synaptic terminals in the bed nuclei of the stria terminalis (BST), a projection area for mPFC cortical neurons. Furthermore, Fgfr2 cKO mice showed secondary decreases in GABAergic neurons in the BST and septum. These data demonstrate that FGFR2 signaling expands the number of excitatory neurons in the mPFC and secondarily influences target neurons in subcortical stations of the limbic system.

Premature birth is a growing and significant public health problem because of the large number of infants that survive with neurodevelopmental sequelae from brain injury. Recent advances in neuroimaging have shown that although some neuroanatomical structures are altered, others improve over time. This review outlines recent insights into brain structure and function in these preterm infants at school age and relevant animal models. These animal models have provided scientists with an opportunity to explore in depth the molecular and cellular mechanisms of injury as well as the potential of the brain for recovery. The endogenous potential that the brain has for neurogenesis and gliogenesis, and how environment contributes to recovery, are also outlined. These preclinical models will provide important insights into the genetic and epigenetic mechanisms responsible for variable degrees of injury and recovery, permitting the exploration of targeted therapies to facilitate recovery in the developing preterm brain.

Three main cellular components have been described in the CNS: neurons, astrocytes, and oligodendrocytes. In the past 10 years, lineage studies first based on retroviruses in the embryonic CNS and then by genetic fate mapping in both the prenatal and postnatal CNS have proposed that astroglial cells can be progenitors for neurons and oligodendrocytes. Hence, the population of astroglial cells is increasingly recognized as heterogeneous and diverse, encompassing cell types performing widely different roles in development and plasticity. Astroglial cells populating the neurogenic niches increase their proliferation after perinatal injury and in young mice can differentiate into neurons and oligodendrocytes that migrate to the cerebral cortex, replacing the cells that are lost. Although much remains to be learned about this process, it appears that the up-regulation of the Fibroblast growth factor receptor is critical for mediating the injury-induced increase in cell division and perhaps for the neuronal differentiation of astroglial cells.

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in CD44 null mice. These results suggest that CD44 is required for the normal development of the hippocampus.

compensate for the lack of p57. Since we did not detect any change in cyclin E mRNA level, increased cyclin/CDK activity might account for the increased cell proliferation. To characterize effects on cortex structure, we performed stereological analysis at E18.5 and found a 15% increase in total volume and 26% increase in total cells. While no change in cell density was observed, the depth of layers I and VI was increased (39% and 19%, respectively). Furthermore, using the layer VI specific marker Tbr1, we found a 40% increase in the mutants at E18.5 and a 2-fold increase in protein by western blotting. Our observations suggest that p57 is a critical regulator of cortical precursor proliferation, and may be determinant of laminar-specific cell production during cortical neurogenesis.