Cis-regulatory control of corticospinal system development and evolution
Open accessAbstract
The co-emergence of a six-layered cerebral neocortex and its corticospinal output system is one of the evolutionary hallmarks of mammals. However, the genetic programs that underlie their development and evolution remain poorly understood. Here we identify a conserved non-exonic element (E4) that acts as a cortex-specific enhancer for the nearby gene Fezf2 (also known as Fezl and Zfp312), which is required for the specification of corticospinal neuron identity and connectivity. We find that SOX4 and SOX11 functionally compete with the repressor SOX5 in the transactivation of E4. Cortex-specific double deletion of Sox4 and Sox11 leads to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. We show evidence supporting the emergence of functional SOX-binding sites in E4 during tetrapod evolution, and their subsequent stabilization in mammals and possibly amniotes. These findings reveal that SOX transcription factors converge onto a cis-acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons.
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Sox binding sites in this enhancer emerged during tetrapod evolution and stabilized in mammals to establish a regulatory network controlling corticospinal tract specification and formation.
“The Sox binding sites in this enhancer emerged during tetrapod evolution and stabilized in mammals to establish a regulatory network that controls corticospinal tract specification and formation.”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shim et al., 2012
In Fezf2, cortex-specific enhancer E4 is essential for corticospinal tract development mediated by SOX4 and SOX11.
“For instance, in the case of Fezf2, a cortex specific enhancer, E4, is essential for corticospinal tract development mediated by SOX4 and SOX11 (Shim et al., 2012).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shim et al., 2012
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References 55 · Cited by 183
- Authors
- Shim, S., Kwan, K. Y., Li, M., Lefebvre, V., & Šestan, N.
- Affiliations
- Yale University (US)
- Corresponding author
- Šestan, Nenad
- Venue
- Nature
- Published
- 2012-05-30
- Volume
- 486
- Issue
- 7401
- Pages
- 74-79
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3375921
- OpenAlex
- W1997052232
- Cited by
- 183
- References
- 55
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 10 · 2023: 7 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 12 · 2018: 9 · 2017: 18 · 2016: 19 · 2015: 19 · 2014: 16 · 2013: 26 · 2012: 5
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Mental Health (MH081896, U01MH081896)
- National Institute of Neurological Disorders and Stroke (R01NS054273, NS 054273)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR54153, R01AR054153)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD045481)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- corticospinal system, Fezf2, SOX4, SOX11, SOX5, cis-regulatory elements, enhancer evolution, neocortex evolution, corticospinal neurons, tetrapod evolution, mammalian brain evolution, transcriptional repression
- MeSH terms
- Animals, Axons, Base Sequence, Binding Sites, DNA-Binding Proteins, Enhancer Elements, Genetic, Mice, Transgenic, Molecular Sequence Data, Nerve Tissue Proteins, Organ Specificity, Spinal Cord, Genetic Variation, Mice, Knockout, Gene Expression Regulation, Developmental, Evolution, Molecular, Neocortex, Mice, SOXC Transcription Factors
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