Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 41, Pages 16021-16026Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806791105
Keywords
neocortex development; postmitotic mechanisms; pyramidal neurons; Sox genes; transcriptional enhancer
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Funding
- National Institutes of Health [NS054273]
- March of Dimes Foundation [6-FY05-73]
- Whitehall Foundation
- Canadian Institutes of Health Research
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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 misrourting 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.
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