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; Alex S Nord; A Jeremy Willsey; Bin Chen; Matthew W State; Vikaas S Sohal; John L R Rubenstein

doi:10.1016/j.neuron.2018.09.027

Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity

Neuron. 2018 Nov 21;100(4):831-845.e7. doi: 10.1016/j.neuron.2018.09.027. Epub 2018 Oct 11.

Authors

Siavash Fazel Darbandi¹, Sarah E Robinson Schwartz², Qihao Qi³, Rinaldo Catta-Preta⁴, Emily Ling-Lin Pai⁵, Jeffrey D Mandell⁶, Amanda Everitt⁶, Anna Rubin¹, Rebecca A Krasnoff⁶, Sol Katzman⁷, David Tastad⁷, Alex S Nord⁴, A Jeremy Willsey⁸, Bin Chen⁷, Matthew W State⁹, Vikaas S Sohal¹⁰, John L R Rubenstein¹¹

Affiliations

¹ Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Neurobiology, Physiology, and Behavior and Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA.
⁵ Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
⁸ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.
¹⁰ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience and Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹¹ Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: john.rubenstein@ucsf.edu.

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 (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.

Keywords: ASD; Tbr1; aggression; anxiety-like behavior; cortical development; development; layer 6; synapses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Cells, Cultured
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / genetics*
Gene Dosage / physiology*
Maze Learning / physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neocortex / chemistry
Neocortex / cytology*
Neocortex / physiology*
Nerve Net / chemistry
Nerve Net / cytology*
Nerve Net / physiology*
T-Box Domain Proteins

Substances

DNA-Binding Proteins
T-Box Domain Proteins
Tbr1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding