Decoding the Building Blocks of Neuronal Diversity

In his iconic book, Cosmos, Carl Sagan wrote that the cerebral cortex is where “matter is transformed into consciousness.” This profound function requires approximately 16 billion neurons that are classified according to their morphology, molecular properties, and connectivity. Interestingly at birth, the majority of neurons in the neocortex, including the highly diverse pyramidal neurons, have been generated. These neurons already possess the instructions that will shape and maintain their individual identity in the mature neocortex.

To resolve the molecular instructions driving pyramidal neuron specification, Molyneaux et al. used antibody-based purification methods to isolate pure populations of subcerebral pyramidal neurons (SCPN), callosal pyramidal neurons (CPNs), and corticothalamic pyramidal neurons (CthPNs) at different stages of embryonic corticogenesis in the mouse. These purified neuronal subtypes were then subjected to whole-transcriptome analyses by high-throughput RNA-sequencing to delineate the transcriptional dynamics that influence and refine neuronal identity during development.

A host of differentially expressed genes, mRNA isoforms, and long noncoding RNAs (lncRNAs) were identified and grouped into gene clusters according to the levels and timing of expression in each neuronal subtype. Among these, Molyneaux and colleagues found that expression of cell surface molecules, even those that are within the same class (i.e. G-protein coupled receptors or metabotropic glutamate receptors), differ between subtypes and are strong indicators of neuronal identity. Furthermore, each neuronal subtype may utilize distinct transcriptional mechanisms (such as the use of multiple promoters and transcriptional start sites) to produce alternative mRNA isoforms of the same gene. For example, expression of one isoform of Lrrtm4, a gene associated with synaptic development, increased in SCPNs while it decreased in CThPNs over the course of corticogenesis.

To date, only a handful of regulatory networks are known to shape neuronal identity, most of which were deduced from studies on the epistatic relationship between pairs of genes. The large-scale approach employed by Molyneaux et al. demonstrates that lineage commitment is a far more complex and multifaceted process, particularly at the transcriptional level. To facilitate further dissection of these findings, the authors developed an interactive database, DeCon. This resource enables investigators to query, visualize, and manipulate the results from these studies. This will also serve as a repository for future transcriptomic data obtained from specific neuronal populations. With this resource and further characterization of each molecular player, a comprehensive understanding of the mechanisms that engineer neuronal diversity in the neocortex will be achieved.

Publication

1. Molyneaux BJ, Goff LA, Brettler AC, Chen HH, Brown JR, Hrvatin S, Rinn JL, Arlotta, P (2015) DeCoN: Genome-wide Analysis of In Vivo Transcriptional Dynamics during Pyramidal Neuron Fate Selection in Neocortex. Neuron 85:1-14. doi: 10.1016/j.neuron.2014.12.024