Determining the molecular function of autism risk gene Deleted in Autism 1

It has recently been reported that hypoxia-inducible factor (HIF) is a master transcription factor that activates genes whose products promote adaptation under low oxygen tension. The brain is one of the heaviest oxygen consumers in our body accounting for 20% of total oxygen consumption. HIF is activated in the developing brain at low brain oxygen levels (hypoxia). Pharmacologic HIF activators increase synaptic plasticity, and have beneficial effects on neurological disorders, such as depression. Similarly, hypoxia has been shown to alleviate ASD-like behaviors in Shank3b-/-mice, an ASD genetic model that exhibits autism-like behaviors. Conversely, HIF inhibition reduces cognitive function, decreases neuronal survival, and induces compulsive-like behavior in mice. This project addresses the question of how HIF controls synaptic plasticity, neuronal function, and leads to a reduction in ASD-like symptoms. The key observation is that DIA-1 appears to catalyze the addition of sugar moieties to the surface of neurexin molecules, which bridge the synaptic gap.