Abstract
BackgroundCortical neurons display dynamic patterns of gene expression during the coincident processes of differentiation and migration through the developing cerebrum. To identify genes selectively expressed by the Eomes + (Tbr2) lineage of excitatory cortical neurons, GFP-expressing cells from Tg(Eomes::eGFP) Gsat embryos were isolated to > 99% purity and profiled.ResultsWe report the identification, validation and spatial grouping of genes selectively expressed within the Eomes + cortical excitatory neuron lineage during early cortical development. In these neurons 475 genes were expressed ≥ 3-fold, and 534 genes ≤ 3-fold, compared to the reference population of neuronal precursors. Of the up-regulated genes, 328 were represented at the Genepaint in situ hybridization database and 317 (97%) were validated as having spatial expression patterns consistent with the lineage of differentiating excitatory neurons. A novel approach for quantifying in situ hybridization patterns (QISP) across the cerebral wall was developed that allowed the hierarchical clustering of genes into putative co-regulated groups. Forty four candidate genes were identified that show spatial expression with Intermediate Precursor Cells, 49 candidate genes show spatial expression with Multipolar Neurons, while the remaining 224 genes achieved peak expression in the developing cortical plate.ConclusionsThis analysis of differentiating excitatory neurons revealed the expression patterns of 37 transcription factors, many chemotropic signaling molecules (including the Semaphorin, Netrin and Slit signaling pathways), and unexpected evidence for non-canonical neurotransmitter signaling and changes in mechanisms of glucose metabolism. Over half of the 317 identified genes are associated with neuronal disease making these findings a valuable resource for studies of neurological development and disease.
Highlights
Cortical neurons display dynamic patterns of gene expression during the coincident processes of differentiation and migration through the developing cerebrum
The ability of neurons to simultaneously navigate through the developing cortex and acquire characteristic phenotypes is likely to depend on dynamic patterns of gene expression during the early postmitotic period
We focused on the neuronal lineage that expresses E14.5 from a reporter transgenic mouse (Eomes) (Tbr2), a transcription factor that is expressed by intermediate precursor cells [19] and has been genetically linked to microcephaly in mouse [20] and human [21]
Summary
Cortical neurons display dynamic patterns of gene expression during the coincident processes of differentiation and migration through the developing cerebrum. Excitatory, or projection, neurons comprise ~85% of the neuronal population in the mature cerebral cortex These neurons share a stereotypical developmental trajectory, with most generated in the neocortical ventricular zone (VZ) and subsequently migrating outward, through complex and changing micro-environments, towards the cortical surface. The ability of neurons to simultaneously navigate through the developing cortex and acquire characteristic phenotypes is likely to depend on dynamic patterns of gene expression during the early postmitotic period
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