The central nervous system has the most cellular diversity of any organ in the body, but how does this diversity arise?

While the presumption is that genetic programs specify each neuron type, our understanding of these programs is in its infancy. To begin uncovering the underlying design principles of neuronal architecture in the brain, scientists from the Nelson Lab at Brandeis University and the HHMI Janelia Research Campus jointly formed the NeuroSeq project to profile genetic programs in a monumental number of neurons throughout the nervous system. Selected neurons were from transgenic animals to facilitate access among the scientific community for future functional studies. While single cell sequencing is the most popular method for transcriptome profiling, its technical limitations only provide a shallow view of molecular profiles. To go deeper, the NeuroSeq program assessed transcription in pools of nearly 200 genetically identified mouse cell types. NeuroSeq captured 80% of single gene copies and could even assess splice isoforms.

What did the NeuroSeq effort find?

Interestingly, two unique classes of genes lie at the heart of adult neuronal identity. Homeobox transcription factors and long genes explain a great deal of the neuronal diversity in the central nervous system. This extends the role of homeobox genes well beyond development and into neuronal identity maintenance. It also highlights long genes as an important class of neuronal identity effectors. Long genes are long due to insertion of foreign elements, and they come with costs, namely increased energy consumption and risk of mutations. These costs seem to be overcome by the benefits of neuronal diversification. We are excited to spotlight the NeuroSeq project in providing a unique resource for future discoveries concerning neuronal diversity and function.

The data resource is available at neuroseq.janelia.org, and the findings are described in a recent paper in eLife. Brandeis-affiliated authors on the paper include Professor Sacha Nelson, former postdoc Ken Sugino PhD ’05 (now at HHMI Janelia), current postdoc Erin Clark, and former research scientist Yasuyuki Shima.