| First Author | Fazel Darbandi S | Year | 2018 |
| Journal | Neuron | Volume | 100 |
| Issue | 4 | Pages | 831-845.e7 |
| PubMed ID | 30318412 | Mgi Jnum | J:267864 |
| Mgi Id | MGI:6269283 | Doi | 10.1016/j.neuron.2018.09.027 |
| Citation | Fazel Darbandi S, et al. (2018) Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity. Neuron 100(4):831-845.e7 |
| abstractText | An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1(layer6) mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b largely rescues the synaptic deficit in Tbr1(layer6) mutant neurons. Furthermore, Tbr1(layer6) heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data from layer 6 neurons and activity of TBR1-bound candidate enhancers provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits. |
