Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 29; pp. 13129 - 13134
• Main Authors: Bedogni, Francesco, Hodge, Rebecca D., Elsen, Gina E., Nelson, Branden R., Daza, Ray A. M., Beyer, Richard P., Bammler, Theo K., Rubenstein, John L. R., Hevner, Robert F., Rakic, Pasko
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20-07-2010; National Acad Sciences
• Subjects: Animals; Autism; Axons; Biological Sciences; Biomarkers - metabolism; Brain; Cell division; Cerebral cortex; Developmental biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Gene expression regulation; Gene Expression Regulation, Developmental; Genes; Genetics; Identity; Mice; Mitosis; Mutation - genetics; Neocortex; Neocortex - cytology; Neocortex - embryology; Neocortex - metabolism; Neurons; Neurons - cytology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Organ Specificity; Progenitor cells; Protein Binding; Regional identity; Transcriptional Activation; Up-Regulation - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1002285107

Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.