The development of the central nervous system involves a series of complex yet tightly-regulated processes, including the formation of synapses, the sites of communication between neurons, and the morphogenesis of the dendritic arbor, where the majority of synaptic contacts occur. Importantly, the misregulation of these processes is a hallmark of many neurodevelopmental disorders, including autism and mental retardation. However, the molecular mechanisms that underlie these structural and functional changes remain largely obscure.

The lab of Prof. Suzanne Paradis at Brandeis is working to identify and characterize molecules that regulate neural development in the rodent hippocampus. A recently accepted manuscript at Developmental Neurobiology by Brandeis Neurocience Ph.D. student Amy Ghiretti and Dr. Paradis uses RNAi in primary hippocampal cultures to identify novel roles for the GTPase Rem2 in several neurodevelopmental processes. The RNAi-mediated decrease of Rem2 leads to the formation of fewer excitatory synapses, and also results in increased dendritic complexity, suggesting that Rem2 functions normally to promote synapse formation and to inhibit dendritic branching. Additionally, the binding of Rem2 to the calcium-binding protein calmodulin was identified as a key interaction that distinguishes the signaling pathways through which Rem2 mediates synapse development and dendritic branching. Overall, this study identifies Rem2 as a novel regulator of several neurodevelopmental processes, and importantly, suggests that Rem2 regulates excitatory synapse development and dendritic morphology via separable and distinct signaling pathways.

Figure: Neurons in which Rem2 protein expression has been decreased by RNAi (top) show increased dendritic branching compared to control neurons (bottom), suggesting Rem2 acts to inhibit branching