POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex

Cereb Cortex. 2013 Nov;23(11):2632-43. doi: 10.1093/cercor/bhs252. Epub 2012 Aug 14.


The upper layers (II-IV) are the most prominent distinguishing feature of mammalian neocortex compared with avian or reptilian dorsal cortex, and are vastly expanded in primates. Although the time-dependent embryonic generation of upper-layer cells is genetically instructed within their parental progenitors, mechanisms governing cell-intrinsic fate transitions remain obscure. POU-homeodomain transcription factors Pou3f3 and Pou3f2 (Brn1 and Brn2) are known to label postmitotic upper-layer cells, and are redundantly required for their production. We find that the onset of Pou3f3/2 expression actually occurs in ventricular zone (VZ) progenitors, and that Pou3f3/2 subsequently label neural progeny switching from deep-layer Ctip2(+) identity to Satb2(+) upper-layer fate as they migrate to proper superficial positions. By using an Engrailed dominant-negative repressor, we show that sustained neurogenesis after the deep- to upper-layer transition requires the proneual action of Pou3fs in VZ progenitors. Conversely, single-gene overexpression of any Pou3f in early neural progenitors is sufficient to specify the precocious birth of Satb2(+) daughter neurons that extend axons to the contralateral hemisphere, as well as exhibit robust pia-directed migration that is characteristic of upper-layer cells. Finally, we demonstrate that Pou3fs influence multiple stages of neurogenesis by suppressing Notch effector Hes5, and promoting the expression of proneural transcription factors Tbr2 and Tbr1.

Keywords: In utero electroporation; Neurogenesis; Upper layer; development; differentiation.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Movement*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / metabolism*
  • Macaca mulatta
  • Matrix Attachment Region Binding Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis*
  • Neurons / metabolism*
  • Octamer Transcription Factor-6 / metabolism
  • POU Domain Factors / metabolism*
  • Repressor Proteins / metabolism
  • Transcription Factors / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Carrier Proteins
  • Cell Cycle Proteins
  • CtIP protein, mouse
  • Hes5 protein, mouse
  • Matrix Attachment Region Binding Proteins
  • Nerve Tissue Proteins
  • POU Domain Factors
  • Repressor Proteins
  • SATB2 protein, mouse
  • Transcription Factors
  • Octamer Transcription Factor-6
  • Pou3f3 protein, mouse
  • Pou3f2 protein, mouse