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Signal transduction

Deleting PTEN for better or worse

Nature Reviews Neuroscience volume 10, page 249 (2009)Cite this article

PTEN regulates neurogenesis by inhibiting the phosphoinositide 3-kinase (PI3K)–AKT signalling pathway; AKT phosphorylates tuberous sclerosis complex (TSC) 1/2, preventing it from suppressing mammalian target of rapamycin complex 1 (mTORC1). Previous studies showed that mice lacking Pten in neurons have enlarged brains and behavioural abnormalities that resemble those seen in people with autism. Parada and colleagues investigated whether manipulation of the PI3K–AKT pathway could reverse the effects of PTEN loss.

Daily administration of the mTOR1 inhibitor rapamycin for 4–6 weeks to young (5–6 week-old), presymptomatic Pten-mutant mice prevented hippocampal and cortical hypertrophy and dendritic overgrowth as well as the loss of neuronal polarity (which can result in ectopic axonal projections) in hippocampal granule cells. In adult (10–12 week-old), symptomatic mutant mice rapamycin significantly reversed the neuronal hypertrophy in and enlargement of the dentate gyrus, but not the loss of polarity. The treatment also prevented the development of increased anxiety and abnormal social behaviour and the occurrence of spontaneous seizures. Finally, the authors showed that Tsc1-knockout mice had an increased brain/body weight ratio and cortical and hippocampal hypertrophy similar to that of Pten-knockout mice, providing more evidence that the PI3K–AKT–mTOR pathway mediates the effects of Pten ablation.

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ORIGINAL RESEARCH PAPERS

  1. Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009)

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  2. Gregorian, C. et al. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. J. Neurosci. 29, 1874–1886 (2009)

    Article  CAS  Google Scholar 

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Authors
  1. Leonie Welberg
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Welberg, L. Deleting PTEN for better or worse. Nat Rev Neurosci 10, 249 (2009). https://doi.org/10.1038/nrn2625

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