| Description |
Neurodevelopmental disorders severely impact an individual's life. Surprisingly, the genetic and cellular cause of over half of intellectual disability cases and more than 80% of autism spectrum disorders remain undiscovered1,2. It is likely that mutations in molecules regulating synapse development play a role in many forms of neurodevelopmental disorders17, yet, the identities and functions of these disease-causing molecules are largely unknown. Several studies recently identified mutations of the Kirrel3 gene in patients with intellectual disability, autism, and Jacobsen's syndrome: a rare genetic disorder that often includes neurodevelopmental impairment1,21,22,23. Kirrel3 is a transmembrane cell adhesion molecule that mediates synapse formation in C. elegans but has an unknown function in mammalian organisms7. Recently, the William's lab began investigation of Kirrel3 in mice. In situ hybridization experiments demonstrated prominent Kirrel3's expression in both neurons of the dentate gyrus (DG) and in scattered GABAergic (GABA) neurons within the CA3 region of the hippocampus6. Additionally, Kirrel3 knockout studies showed that loss of Kirrel3 elicited over-excitation of the CA3 region of the hippocampus6. These findings suggest that Kirrel3 plays a role in hippocampal circuitry formation. Here I investigate Kirrel3's function in synapse formation in the mouse hippocampus via two aims: first, an investigation of Kirrel3's role in regulating synaptic architecture; second, a study of Kirrel3's binding partners for possible insights into the Kirrel3 dependent synapse formation. I find that Kirrel3 knockouts decrease synapse formation between DG mossy fiber filopodia onto CA3 GABA neurons. This finding suggests Kirrel3 directs synapse formation of DG mossy fiber filopodia onto CA3 GABA neurons, and could explain the over-excitation previously seen in Kirrel3 knockouts. Secondly, to investigate the mechanism of Kirrel3's dependent synapse formation, I developed methods to investigate and identify Kirrel3 binding partners using co-immunoprecipitation. Using those methods, I tested a promising binding partner, CASK, identified from the current literature for binding to Kirrel3. The test was negative for protein interaction but using my developed methodology, I will conduct an unbiased proteomics screen to identify Kirrel3 binding partners. Combined, these data provides novel insights into Kirrel3 alteration-dependent neurodevelopmental disorders. |
