Role of a novel PRCI complex in neurodevelopment and autism neurobiology

  • Awarded: 2015
  • Award Type: Research
  • Award #: 346164

Mutations in the autism susceptibility candidate 2 gene (AUTS2) have long been linked with autism spectrum disorder (ASD) and several neurodevelopmental abnormalities. However, the molecular mechanisms by which AUTS2 functions in normal brain development and how it goes awry in ASD has remained elusive.

Converging evidence from Danny Reinberg’s laboratory and others has begun to indicate that AUTS2 functions to drive the expression of genes important for early brain development. In their most recent study, Reinberg and his colleagues found that AUTS2 activates genes in the developing brain by associating with a polycomb repressive complex 1 (PRC1) and transforming this transcriptionally repressive complex into one that is transcriptionally active1.

In the current project, the researchers will expand on their previous study to investigate the function of AUTS2 within specific regions of the brain in order to understand how this protein can regulate neuronal function and ASD-associated phenotypes. Because AUTS2 is known to be associated with other proteins in neurons as part of a complex, Reinberg and his team will analyze in detail the nature of these complexes using an in vitro cortical neuron differentiation system. They plan to ascertain how these complexes modulate gene expression by investigating how they are targeted to specific genes via the interaction with DNA binding proteins. Finally, they plan to study AUTS2 conditional knockout mice to pinpoint specific brain regions responsible for the effects caused by mutations that disrupt AUTS2 function.

Taken together, findings from the biochemical, neurobiological and behavioral analyses are expected to provide mechanistic insight into how the interplay between chromatin machinery and transcriptional programs go awry in ASD.

 

References

  1. 1.Gao Z. et al. Nature 516, 349-354 (2014) PubMed
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