Astroglial PTEN Loss Disrupts Neuronal Lamination by Dysregulating Radial Glia-guided Neuronal Migration

Department of Pharmacology and Neuroscience, Institute for Alzheimer's Disease and Aging Research, University of North Texas Health Science Center at Fort Worth, TX 76107, USA.
Aging and Disease (Impact Factor: 3.07). 06/2013; 4(3):113-26.
Source: PubMed


PTEN plays an important role not only in tumorigenesis but also in the normal development of central nervous system. PTEN loss in neural progenitor cells during embryogenesis disrupts migration and proper formation of the brain laminar structure. We generated a conditional PTEN knockout mouse by crossing mice that express Cre recombinase driven by the human GFAP promoter to a floxed PTEN gene to investigate the role of astroglial PTEN signaling pathway in neuronal patterning and lamination. We found PTEN loss not only in astroglial cells, but also in radial glia-derived neurons in hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice showed progressive brain enlargement with cellular disorganization that occurred predominantly in hippocampus and cerebellum and died by postnatal day 20. Confocal images show that nestin-positive radial glial cells were observed in the hippocampus, cortex, and cerebellum at postnatal day 0 in homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp), but not in heterozygous hGFAP-Cre(+/-)/PTEN(loxp/-) and hGFAP-Cre(-/-)/PTEN(loxp/loxp) mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mouse eyes, which lack radial glial lineage, were able to develop normal architectonics after birth. In addition, we also found that neuronal progenitor migration was defected at postnatal day 0 in homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) mice. These results suggest that PTEN has a critical role in regulating radial glial differentiation, proliferation, maturation, and eventually neuronal patterning in central nervous system in a spatio-temporal dependent manner.

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Available from: Gourav Roy Choudhury, Jul 12, 2014
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    • "It is possible that the lack of effect on migration could be due to inefficient NEX1Cre-mediated deletion of PTEN in these cells. Additional analyses of cortical structure using Cre recombinases that target earlier steps in neurogenesis (Emx1Cre and hGFAP-Cre) do find significant alterations in cortical organization and hippocampal radial glial persistence, respectively (Lehtinen et al., 2011; Wen et al., 2013). "
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