How a Nervous System is Maintained

Researchers have mapped how transcriptional programming specifies C. elegans neurons.

Model systems in biology have led the way into knowledge of body development. Fruit flies have been the target of intensive work on the genetic origins of morphogenesis and body plan specification, finding successive action by maternally deposited proteins or mRNAs, gap genes, pair rule genes, and homeotic genes to specify ever finer segments of the body. 

An even simpler model system was later developed, in the tiny worm C. elegans, a nematode, which is smaller, faster-developing than the fruit fly, and also transparent. This organism is attractive for some neurobiology studies, (despite lacking a brain), since its nervous system is both simple and stereotypical- every worm has 302 neurons, of 118 types, laid out in pretty much the same pattern, all easily visible. 

The neurons of C. elegans, in overview. Only the cell body locations are shown, not their various axonal and dendritic processes.

A recent paper therefore looked into the question of how these neurons are specified- how they maintain their identity through the life of the worm, after their original development. The fruit fly genes mentioned above that lay out the body plan are almost all transcription regulators- proteins that regulate the expression of other genes by binding near them and turning on (or off) transcription. A cascade of such regulators allows complex programs of refinement and specification to be carried out, to the point that individual cells are told what they are supposed to be and what features they are supposed to express. These patterns of transcription eventually get cast in stone by the durable repression of unneeded genes, and feedback loops that perpetuate the expression of whatever ones at the end are required to maintain the particular specified type. These are also transcription regulators acting at the end of the line of the developmental pathway, and are called "terminal selectors", since they regulate /select the final sets of genes to be expressed in that cell type which manifest whatever it is supposed to be. 

So a question is- what kind of terminal selectors are active in the stereotyped neurons of C. elegans? Are there just a few for each neuron, used broadly to control all its distinctive genes, or are there many different ones deployed in a complex combinatorial code of transcription regulators to control the final gene expression and the cell type? What they found was that these worms use mostly the former method, and much less the latter. But there can be over 20 such regulators deployed in combination to set up some of these neuronal cells.

For each neuron type (top graph, bottom axis), the associated transcriptional regulators are either common (blue) or rare and particular (green). Common regulators are used to broadly bind to and activate many or most of that neuron's specifically expressed genes. The bottom graph shows the various regulators (bottom axis), and counts how many neuron types they operate in (Y-axis). Some of these regulators are used by many neurons, yet by their cooperation with other regulators can be relied on to specify a particular cell type.

The methods these researchers use are two-fold. One is to sequence all the RNAs of each specific neuron (generally called single cell sequencing). This was used to find all the specifically (differentially) expressed genes of each neuronal cell type, whose upstream regions were then investigated to find the binding sites for all the known transcription regulators of C. elegans. This catalog of target binding sites, genes and their binding regulators could then be compiled to ask whether each cell type had a characteristic pattern ... and generally they do. A second method was to consult a previously developed collection of many "reporter" genes, which had each been fused to bit of DNA encoding a fluorescent protein, which then were screened as being expressed specifically in one or another neuron of C. elegans. This collection of 1000 genes was likewise scanned for its regulatory sites and binding transcription regulators, and the authors found completely concordant results- that here too. the same combinations of regulators were used time and again to activate the specific genes of each neuron. 

Analysis of one gene, and one regulator, through evolutionary time. One key analysis to find regulator sites on a gene was to ask whether its sites were conserved in related species. Here, the ODR-7 DNA-binding regulator has binding sites both upstream and within the olrn-1 gene. Sites are shown in purple, the gene transcription start is shown with the big arrow at top, and the gene's coding exons are shown in black blocks downstream of the start site. The locations of the sites are not well conserved, but their presence is quite well conserved, here on a gene that is expressed in AWS neurons, and necessary for them to occur. 

So development, specification, and maintenance of the body are encoded by the genome largely via a program of regulators that are placed where they are supposed to be, and then successively activate, out of the genome, further parts of the control series in defined regions, and finally regulate the genes required to manifest the body plan in particular places, by expressing (or repressing) genes for the ion channels, cytoskeletal formation, neurotransmitters, and all other specific bric-a-brac of each cell type.

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