Hobert Lab explores new mechanisms of nervous system development
One of the most elusive questions in biology is how our developing brains properly form the trillions of connections, or synapses, that comprise our nervous systems. There are over one hundred billion neurons in the human brain, with over a hundred trillion synapses formed between them, so the proper assembly of a nervous system requires complex coordination between neurons. Essential to this coordination, each neuron needs to signal its unique identity to surrounding neurons to navigate where it should send out projections and form synapses. In a new Science Advances paper from the Hobert Lab, former biological sciences PhD student Dr. Maryam Majeed and current postdoctoral researcher Dr. Chien-Po Liao report the surprising role played in this process by a family of adhesion molecules in this process.
Researchers have some clues as to what types of signals neurons provide as their unique identifiers during development, but lack a comprehensive understanding of these “identifier signals”. One compelling candidate is a family of adhesion proteins called cadherins. Cadherins are known to stick out from cell surfaces to enable interactions with nearby cells, and there is compelling evidence of their role in providing “identifier signals” in parts of the mammalian nervous system. The researchers conducted their studies in the roundworm C. elegans, which grows up to only 1mm in length (barely visible by eye), and has only 302 fully mapped neurons, making it an extremely powerful tool to study the development of an entire nervous system.
Furthermore, C. elegans have 12 different cadherins (humans have a whopping 113) which makes sense for a more complex brain that would presumably require a more complex developmental program. Therefore, the researchers asked whether different combinations of cadherins were sufficient to provide the neuronal “identifier signals” needed to build an entire brain.
To study this, they characterized the expression of all 12 cadherins in all 302 neurons of C. elegans, across development. They found that unique combinations of cadherin expression are not pervasively found across the brain, thus cadherins are not the end-all be-all “identifier signals” during development. However, they found that cadherins play important and previously unknown functions at many scales of brain development and that their roles at different scales could be dissociated. In other words, a cadherin protein could be only required for neuronal projections and not synapse development, and vice versa.
Interestingly, neurons that express more selective cadherins, that is the cadherins expressed only in a handful of neurons, are more likely to communicate with one another. This communication is based on overlaying cadherin expression with the C. elegans wiring diagram. For instance, cadherin-9 is expressed in only 18 of the 302 neurons, and those 18 cells form connections with one another. Furthermore, when Dr. Majeed and her colleagues removed cadherin-9 from C. elegans, they found defects in some connections formed between those 18 cells, showing that at least some cadherins provide identifier signals to guide cells to form the right synapses.
Additionally, Dr. Majeed and her colleagues found that another cadherin, cadherin-5, is important in a specific type of synapse formation when the worms are exposed to stressors, such as starvation, overpopulation, and high temperatures. When worms endure periods of stress during development, they have an incredible ability to pause development and enter an adaptive state called “dauer,” in which they can survive for months without food. Entering dauer requires some remodeling of the worms’ nervous system, and cadherin-5 appears to play an important role in the formation of these new, adaptive connections.
Altogether, this paper provides a comprehensive atlas of cadherin expression in C. elegans and outlines some new roles of cadherins in nervous system development. While cadherins are not entirely responsible for providing unique neuronal “identifier signals” in the developing brain, this paper gives a wealth of information on a gene family that has expanded across phyla and plays many interesting roles in brain development.