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Gene expression differences drive motor neuron lineage decisions

The pathways driving neuronal development and function are generally well characterized. However, how the diversity of neuronal subtypes is established and maintained is currently poorly understood. A new study published in Neuron using advanced single cell sequencing methods has found a genetic basis for how motor neurons can exhibit diversity in both synaptic structure and function.

Same but different

Two key types of neurons are the tonic and phasic motor neurons. Tonic motor neurons typically innervate single muscles and control quick bursts of muscle contraction, while phasic motor neurons coordinate the contraction of groups of muscles over longer periods of time. While these two neuron types perform the same function on a basic level, they show differences in morphology, sensitivity to chemical inputs and synaptic plasticity. It is currently unknown how the decision to become a tonic or phasic motor neuron is made, or which genes are key to driving this decision, However, researchers at The Picower Institute for Learning and Memory, MIT, aimed to find out.

Genetic diversity

Using Drosophila models, researchers studied how motor neurons displaying tonic and phasic synaptic output differed at the transcriptome level. By using single neuron Isoform-Patchseq technology on motor neurons taken from the exact same location in hundreds of flies, the group were able to identify 822 differentially expressed genes (DEGs) between the two types of motor neurons. From this DEG list, 35 genes were related to axonal pathfinding, while others were related to establishing the structure and function of synapses.

A number of individual key genes for specific functions were also identified, which the group investigated further to establish their importance in this lineage deciding process. Notably, Wnt4, a gene that participates in motor neuron-specific synaptic growth programmes, was found to have 40x higher expression in tonic compared to phasic motor neurons. Disruption of this gene expression was found to reduce synaptic growth. Another key gene, Cbp53E, which regulates resting calcium levels, was found to be 30x higher in phasic compared to tonic motor neurons.

Important shapes

A further difference between the two motor neuron types lies in their active zones (AZs), synaptic sites with specific shapes which prompt release of the neurotransmitter glutamate. Researchers found that tonic and phasic motor neurons have different shaped AZs, with tonic neurons displaying round AZs, while phasic neurons display triangular or star shaped AZs.

Troy Littleton, Menicon Professor of Neuroscience and leader of the research group, hypothesises that the phasic neuron’s AZ shape may allow for more calcium ions to enter, resulting in differences in the amount of glutamate released at the synapse and the resulting strength of the signal. This difference in calcium levels may also be related to the overexpression of Cbp53E noted in phasic motor neurons, highlighting a key difference in the structure and function of these two motor neuron types.

More to uncover

The molecular logic that determines the unique features of tonic and phasic synaptic diversity is still largely unknown, but the characterisation of these DEGs is a promising step towards understanding the mechanisms behind this plasticity. While there is more work to be done, these findings provide insights into how unique transcriptomes drive the functional and morphological differences found between motor neuron subtypes.

More on these topics

Gene Expression / motor neuron / Sequencing