NeuroSeq and cell diversity in the nervous system

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, 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.

Genome illustration

Mei Zeng Receives Genome Customization Award

Mei Zeng, a postdoc in Nelson Lau’s lab (Biology) has been selected to receive a postdoctoral fellowship award – the Genome Customization Award (TGCA) from Cellectis Bioresearch. The TGCA award was established by Cellectis Bioresearch in 2010 with the goal of spreading the use of meganucleases for genome customization throughout the life sciences

Meganucleases are endodeoxyribonucleases characterized by a large recognition site (12 to 40 base pairs) — so large that it  generally only occurs once in any given genome. The Lau group will apply the custom meganucleases to improve transgenesis of Xenopus tropicalis for RNA interference methodologies. The most widely used transgenesis method utilizes the yeast meganucleases I-SceI which cuts both the transgene vector and an unknown site in the genome into which the transgene gets integrated. This method has several limitations: it requires a large number of embryos for injection and screening,  the integration sites cut by I-Sce-I are unknown and likely stochastic, and it ultimately produces only 5-10% of germline transmission. The custom meganucleases engineered by Cellectis Bioresearch target a known single site (24bp) within the genome, allowing for increased specificity and efficiency of transgene intergration. Mei and colleagues hope to use the rational design to enforce the systemic constitutive expression of a short hairpin RNA cassette in a vertebrate model.

Marc Le Bozec, CEO of Cellectis Bioresearch, presented the award to Drs. Nelson Lau and Mei Zeng on March 16, 2011 at the grand opening of Cellectis Bioresearch Inc facilities in Cambridge, Massachusetts.

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