Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity

Siavash Fazel Darbandi, Sarah E. Robinson Schwartz, Qihao Qi, Rinaldo Catta-Preta, Emily Ling Lin Pai, Jeffrey D. Mandell, Amanda Everitt, Anna Rubin, Rebecca A. Krasnoff, Sol Katzman, David Tastad, Alexander Nord, A. Jeremy Willsey, Bin Chen, Matthew W. State, Vikaas S. Sohal, John L.R. Rubenstein

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 (Tbr1layer6 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 Tbr1layer6 mutant neurons. Furthermore, Tbr1layer6 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.

Original languageEnglish (US)
Pages (from-to)831-845
Number of pages15
JournalNeuron
Volume100
Issue number4
DOIs
StatePublished - Nov 21 2018

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Keywords

  • aggression
  • anxiety-like behavior
  • ASD
  • cortical development
  • development
  • layer 6
  • synapses
  • Tbr1

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Fazel Darbandi, S., Robinson Schwartz, S. E., Qi, Q., Catta-Preta, R., Pai, E. L. L., Mandell, J. D., Everitt, A., Rubin, A., Krasnoff, R. A., Katzman, S., Tastad, D., Nord, A., Willsey, A. J., Chen, B., State, M. W., Sohal, V. S., & Rubenstein, J. L. R. (2018). Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity. Neuron, 100(4), 831-845. https://doi.org/10.1016/j.neuron.2018.09.027