ERK signaling in autism associated with 16p11.2 copy number variation

  • Awarded: 2012
  • Award Type: Explorer
  • Award #: 249475

The most common genetic cause of autism is the deletion or duplication of a small region of human chromosome 16. Although these genetic changes account for only about 1 percent of all cases of autism, they predictably result in autism symptoms.

Because there are only 27 genes in this chromosomal region, it provides an opportunity to identify the genes responsible for the deficits in brain development and the characteristic behavioral changes that typify autism spectrum disorders.

Using a new mouse model (16p11.2del) that mimics human 16p11.2 loss, Gary Landreth and his colleagues at Case Western Reserve University in Cleveland, Ohio, are investigating which of the deleted genes leads to developmental defects in the brain. They have focused on the actions of MAPK3, which participates in the transmission and translation of neuronal signals into changes in cellular metabolism and physiology.

The MAPK3 gene is positioned within the deleted chromosomal region and encodes the signaling molecule ERK1. Significantly, genetic perturbation of the ERK signaling pathway is associated with a number of syndromes that are characterized by impaired cognition, psychiatric disease and an array of developmental abnormalities, including autism.

The investigators previously showed that mice lacking ERK1/2 exhibit behavioral deficits and altered cortical anatomy. They investigated whether 16p11.2del mice exhibit altered ERK activity and abnormal cortical structure. Indeed, they found that the cortex of the 16p11.2del mice shows changes in the number and distribution of neurons, in a pattern similar to that observed in ERK mutant mice. They also found that the enzymatic activity of the ERKs is elevated.

Importantly, the 16p11.2del mice exhibit anxiety-like behaviors and memory deficits, but are unimpaired in social interaction tests. The outcomes of this pilot project provide a rationale to explore the linkage between the ERK signaling cascade and autism using 16p11.2del mice.

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