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Cis-regulatory control of corticospinal system development and evolution.

Nature | May 30, 2012

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.

Pubmed ID: 22678282 RIS Download

Mesh terms: Animals | Axons | Base Sequence | Binding Sites | DNA-Binding Proteins | Enhancer Elements, Genetic | Evolution, Molecular | Gene Expression Regulation, Developmental | Genetic Variation | Mice | Mice, Knockout | Mice, Transgenic | Molecular Sequence Data | Neocortex | Nerve Tissue Proteins | Organ Specificity | SOXC Transcription Factors | Spinal Cord

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Associated grants

  • Agency: NIMH NIH HHS, Id: U01 MH081896-04
  • Agency: NINDS NIH HHS, Id: NS054273
  • Agency: NICHD NIH HHS, Id: R01 HD045481
  • Agency: NIAMS NIH HHS, Id: R01 AR054153
  • Agency: NINDS NIH HHS, Id: R01 NS054273-08
  • Agency: NINDS NIH HHS, Id: R01 NS054273
  • Agency: NIMH NIH HHS, Id: U01 MH081896
  • Agency: NICHD NIH HHS, Id: R01 HD045481-05
  • Agency: NIAMS NIH HHS, Id: AR54153
  • Agency: NIMH NIH HHS, Id: MH081896

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GenePaint.org

A digital atlas of gene expression patterns in the developing and adult mouse. Several reference atlases are also available through this site. Expression patterns are determined by non-radioactive in situ hybridization on serial tissue sections. Sections were labeled using non radioactive in situ hybridization with riboprobes and annotated for level of gene expression (not detected, weak, medium, strong) and pattern (ubiquitous, regional, scattered). Sections are available from several developmental ages: E10.5, E14.5 (whole embryos), E15.5, P7 and P56 (brains only). To retrieve expression patterns, search by gene name, site of expression, GenBank accession number or sequence homology. For viewing expression patterns, GenePaint.org features a virtual microscope tool that enables zooming into images down to cellular resolution.

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