This week, the Dart Neurosciences Seminar hosts Joshua Sanes, a professor of molecular and cellular biology at Harvard. Dr. Sanes’ scientific interests revolve around key fundamental questions in systems neuroscience: How do circuits form in development, how do they change over maturity, and how do they function to process signals in adulthood? To this end, Dr. Sanes has spent many years probing the retina as a model for the rest of the brain. In particular, he has been a pioneer in identifying retinal subtypes, probing their connectivity dynamics, and manipulating different parts of the circuit to evaluate their importance.
Recently, Dr. Sanes and his lab members have focused on molecules that play in role in forming these synaptic connections- namely the cadherin superfamily. It has been known that in the retina, cells of the same subtype are spaced apart such that few neighboring cells are of the same subtype. However, a mechanism for the formation of such a mosaic was unknown. In a 2012 Nature paper, Jeremy Nay, Monica Chu, and Joshua Sanes identified two transmembrane proteins found in a subset of retinal cells that regulate positioning of Starburst Amacrine Cells (SACs) and Horizontal Cells (HCs) during development. In this paper, the group showed that these two proteins (MEGF10 and MEGF11) act as repulsive ligands, where cells that express these proteins will repel other cells expressing the same protein. They further showed that the protein is required as part of both the ligand and receptor sides, a homotypic interaction. This results in ‘exclusion zones’ around a particular cell, creating the mosaic spacing seen between cells of the same subtype in the retina. While the previous hypothesis was that each subtype had a unique ligand-receptor signal, these results show how two proteins work cooperatively to create a repulsive mosaic for horizontal cells, and how one of those proteins (MEGF10) also acts on SACs. As these two cell types are in different layers, it opens up the possibility that these mosaic ligands are layer specific, reducing the necessary diversity to create a structures, mosaic map in the retina.
What is the importance of elucidating these mechanisms? As Dr. Sanes mentions frequently, the retina is an easy-to-access proxy for other brain areas. There are numerous examples of neuronal arrays throughout the CNS. This first evidence of homotyptic repulsion could lead to an understanding how uniformity is established in the brain.
Since the 1970s, Dr. Sanes has approached the question of neural synapses in different ways. From neuromuscular junctions in frogs, to discovering and cloning the protein lamin B2, he has tried to explore the molecules that form the junction, and how disturbing the system affects the synapse. With Jeff Lichtman, an expert in live imaging, Dr. Sanes hopes to continue probing the nature of cell-to-cell connections and synapse formation and change over time. In recent years, this duo has gained fame for the creation of ‘brainbow’ mice, lines of transgenic mice that express varying amounts of three fluorophores in each cell, creating a veritable rainbow of colors that allows visual separation of each cell and its axon from neighboring cells. The entire field of neuroscience will benefit as Dr. Sanes continues to push boundaries in the fields of development of retinal architecture, synapse formation, and circuit evolution.
If you’d like to find out more about these studies, come listen to Dr. Joshua Sanes on Tuesday, March 3rd in the Center for Neural Circuits and Behavior Marylin C. Farquhar Conference Room!
(Sahil Shah is an M.D./Ph.D. student in the lab of Jeffrey Goldberg. He is studying protein synthesis and transport in the retinal ganglion cell as it relates to aging and disease.)
Kay, J. N., Chu, M. W., & Sanes, J. R. (2012). MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons. Nature, 483(7390), 465-469.