SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons.
Neocortical projection neurons exhibit layer-specific molecular profiles and axonal connections. Here we show that the molecular identities of early-born subplate and deep-layer neurons are not acquired solely during generation or shortly thereafter but undergo progressive postmitotic refinement mediated by SOX5. Fezf2 and Bcl11b, transiently expressed in all subtypes of newly postmigratory early-born neurons, are subsequently downregulated in layer 6 and subplate neurons, thereby establishing their layer 5-enriched postnatal patterns. In Sox5-null mice, this downregulation is disrupted, and layer 6 and subplate neurons maintain an immature differentiation state, abnormally expressing these genes postnatally. Consistent with this disruption, SOX5 binds and represses a conserved enhancer near Fezf2. The Sox5-null neocortex exhibits failed preplate partition and laminar inversion of early-born neurons, loss of layer 5 subcerebral axons, and misrouting of subplate and layer 6 corticothalamic axons to the hypothalamus. Thus, SOX5 postmitotically regulates the migration, postmigratory differentiation, and subcortical projections of subplate and deep-layer neurons.
Kwan
Kenneth Y
KY
Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
Lam
Mandy M S
MM
Krsnik
Zeljka
Z
Kawasawa
Yuka Imamura
YI
Lefebvre
Veronique
V
Sestan
Nenad
N
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement; D022081:Cell Surface Extensions; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D019579:Neocortex / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D012097:Repressor Proteins / Q000235:genetics; D055755:SOXD Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
C511143:Bcl11b protein, mouse; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; D025521:Tumor Suppressor Proteins