POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex.
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.
Department of Neurobiology, Yale University School of Medicine and Kavli Institute for Neuroscience, 06510 New Haven, CT, USA.
Martin H
MH
Dominguez
Albert E
AE
Ayoub
Pasko
P
Rakic
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D008253:Macaca mulatta; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D050816:Octamer Transcription Factor-6 / Q000378:metabolism; D050809:POU Domain Factors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D036961:Matrix Attachment Region Binding Proteins; D009419:Nerve Tissue Proteins; D050816:Octamer Transcription Factor-6; D050809:POU Domain Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C501070:RBBP8 protein, mouse; C489685:Hes5 protein, mouse; C501473:SATB2 protein, mouse; C074065:Pou3f3 protein, mouse; C074066:Pou3f2 protein, mouse