Convergent signaling pathways linking PTEN and MeCP2, two risk genes for autism spectrum disorders

  • Awarded: 2016
  • Award Type: Explorer
  • Award #: 437633

Aberrant PI3K/PTEN signaling during brain development has emerged as a key determining factor in autism spectrum disorders (ASDs). Germline mutations in PTEN have been found in 20 percent of individuals with ASD and severe macrocephaly. Indeed, there is a growing consensus that deregulation of PI3K/PTEN signaling signifies a convergent pathway for behavioral abnormalities associated with various neurodevelopmental disorders.

Recent reports also suggest the involvement of PI3K/PTEN signaling in Rett syndrome, a postnatal neurodevelopmental disorder caused by mutations in the global transcriptional regulator MeCP2. Despite diverse genetic origins and behavioral phenotypes, loss of either PTEN or MeCP2 results in strikingly similar neuronal alterations, including effects on soma size, dendritic spine morphology and the density and properties of glutamatergic synapses. These data suggest that PTEN and MeCP2 may converge on a shared signaling mechanism during neuronal development.

Britta Eickholt proposes to understand the interdependence between PTEN/PI3K and MeCP2 during neural differentiation and circuit formation. Preliminary studies from her laboratory, using pharmacology and a PTEN knockout mouse model, suggest that altered PI3K/PTEN signaling in neurons regulates MeCP2 function.

Eickholt and her colleagues now seek to identify the precise roles played by cytoplasmic and nuclear PTEN in regulating MeCP2 function during neural differentiation and circuit formation. Eickholt’s team will analyze both the role of PI3K/PTEN as an extrinsic cytoplasmic signal mediating MeCP2 transcriptional changes and the effects of PTEN/MeCP2 in the nucleus. To further study the functional interplay between PTEN and MeCP2, the researchers will use PTEN-, MeCP2- and PTEN/MeCP2-knockout mouse models to compare neuronal growth and maturation deficits, and identify effects mediated by cytoplasmic versus nuclear PTEN. The results of this research will aid our understanding of common neurodevelopmental pathways disrupted in ASDs, and point toward potential candidates for future therapeutic intervention.

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