A network of genetic repression and derepression specifies projection fates in the developing neocortex
Open accessAbstract
Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes— Fezf2, Ctip2, Tbr1 , and Satb2 —regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2 , and Satb2 , that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4 , and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1 , implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2–5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.
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Interactions of several genes with Tbr1 determine corticothalamic projection of layer VI neurons, callosal projection of superficial cortical layer neurons, and subcortical projection of layer V neurons.
“Complex interactions of several genes with Tbr1 determine the corticothalamic projection of layer VI neurons, callosal projection of neurons in the cortical superficial layers [335] and subcortical projection of layer V neurons [50, 142, 232].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [335]
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- Authors
- Srinivasan, K., Leone, D. P., Bateson, R. K., Dobreva, G., Kohwi, Y., Kohwi-Shigematsu, T., Grosschedl, R., & McConnell, S. K.
- Affiliations
- Stanford University (US)
- Max Planck Society (DE)
- Lawrence Berkeley National Laboratory (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-11-09
- Volume
- 109
- Issue
- 47
- Pages
- 19071-19078
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3511157
- OpenAlex
- W2124289307
- Cited by
- 171
- References
- 35
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 18 · 2021: 8 · 2020: 10 · 2019: 15 · 2018: 9 · 2017: 11 · 2016: 16 · 2015: 19 · 2014: 16 · 2013: 13
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Harvard University
- National Institutes of Health
- National Institute of Mental Health (K99MH086720)
- National Eye Institute (EY 08411, R01EY008411)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- neocortex development, Fezf2, CTIP2, Tbr1, SATB2, mutual repression, callosal projections, subcortical projections, EphA4, AUTS2, hereditary spastic paraplegia, autism susceptibility, neurodevelopmental disorders, cortical layers
- MeSH terms
- Netrin Receptors, Alkaline Phosphatase, Animals, Axons, Cerebral Cortex, Cytoskeletal Proteins, DNA-Binding Proteins, Isoenzymes, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Protein Binding, Receptors, Cell Surface, Repressor Proteins, Thalamus, Transcription Factors, Cell Adhesion Molecules, Neuronal, Gene Expression Regulation, Developmental, Neocortex, T-Box Domain Proteins, Tumor Suppressor Proteins, Receptor, EphA4, Mice, Basic Helix-Loop-Helix Proteins, Gene Regulatory Networks, Genetic Loci, GPI-Linked Proteins
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