Article

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 06/2013; 4(3):113-26.
Source: PubMed

ABSTRACT 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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    ABSTRACT: This review will consider the impact of compromised PTEN signaling in brain patterning. We approach understanding the contribution of PTEN to nervous system development by surveying the findings from the numerous genetic loss-of-function models that have been generated as well as other forms of PTEN inactivation. By exploring the developmental programs influenced by this central transduction molecule, we can begin to understand the molecular mechanisms that shape the developing brain. A wealth of data indicates that PTEN plays critical roles in a variety of stages during brain development. Many of them are considered here including: stem cell proliferation, fate determination, polarity, migration, process outgrowth, myelination and somatic hypertrophy. In many of these contexts, it is clear that PTEN phosphatase activity contributes to the observed effects of genetic deletion or depletion, however recent studies have also ascribed non-catalytic functions to PTEN in regulating cell function. We also explore the potential impact this alternative pool of PTEN may have on the developing brain. Together, these elements begin to form a clearer picture of how PTEN contributes to the emergence of brain structure and binds form and function in the nervous system.
    Frontiers in Molecular Neuroscience 04/2014; 7(35). DOI:10.3389/fnmol.2014.00035
    This article is viewable in ResearchGate's enriched format

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