Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex

Cell Rep. 2019 Oct 15;29(3):645-658.e5. doi: 10.1016/j.celrep.2019.09.007.


Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity of primate cortical neurons is still unresolved. Here, we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity. Indeed, while Dbx1 is expressed in highly restricted cortical progenitors in the mouse ventral pallium, it is maintained in neurons in primates. Phenocopy of the primate-like Dbx1 expression in mouse cortical progenitors induces ectopic Cajal-Retzius and subplate (SP) neurons, which are transient populations playing crucial roles in cortical development. A conditional expression solely in neurons uncouples mitotic and postmitotic activities of Dbx1 and exclusively promotes a SP-like fate. Our results highlight how transcriptional changes of a single fate determinant in postmitotic cells may contribute to the expansion of neuronal diversity during cortical evolution.

Keywords: Cajal-Retzius neurons; Dbx1; cortical evolution; postmitotic; primate-specific cis-regulatory elements; subplate neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution*
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Embryo, Mammalian / metabolism
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Macaca
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Pregnancy
  • T-Box Domain Proteins / metabolism


  • Dbx1 protein, mouse
  • Eomes protein, mouse
  • Homeodomain Proteins
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • T-Box Domain Proteins