Neocortical Sox9+ radial glia generate glutamatergic neurons for all layers, but lack discernible evidence of early laminar fate restriction.

Glutamatergic neurons in the cerebral cortex are derived from embryonic neural stem cells known as radial glial progenitors (RGPs). Early RGPs, present at the onset of cortical neurogenesis, are classically thought to produce columnar clones of glutamatergic neurons spanning the cortical layers. Recently, however, it has been reported that a subset of early RGPs may undergo early commitment to upper layer neuron fates, thus bypassing genesis of deep layer neurons. However, the latter mode of early RGP differentiation was not confirmed in some other studies, and remains controversial. To further investigate the clonal output from early RGPs, we employed genetic lineage tracing driven by Sox9, a transcription factor gene that is expressed in all early RGPs. We found that early RGPs produced columnar clones spanning all cortical layers, with no evidence of significant laminar fate restriction. These data support the classic progressive restriction model of cortical neurogenesis, and suggest that early RGPs do not undergo early commitment to only upper or lower layer fates.

Control of Neuronal Development by T-Box Genes in the Brain.

T-box transcription factors play key roles in the regulation of developmental processes such as cell differentiation and migration. Mammals have 17 T-box genes, of which several regulate brain development. The Tbr1 subfamily of T-box genes is particularly important in development of the cerebral cortex, olfactory bulbs (OBs), and cerebellum. This subfamily is comprised of Tbr1, Tbr2 (also known as Eomes), and Tbx21. In developing cerebral cortex, Tbr2 and Tbr1 are expressed during successive stages of differentiation in the pyramidal neuron lineage, from Tbr2+ intermediate progenitors to Tbr1+ postmitotic glutamatergic neurons. At each stage, Tbr2 and Tbr1 regulate laminar and regional identity of cortical projection neurons, cell migration, and axon guidance. In the OB, Tbr1 subfamily genes regulate neurogenesis of mitral and tufted cells, and glutamatergic juxtaglomerular interneurons. Tbr2 is also prominent in the development of retinal ganglion cells in nonimage-forming pathways. Other regions that require Tbr2 or Tbr1 in development or adulthood include the cerebellum and adult dentate gyrus. In humans, de novo mutations in TBR1 are important causes of sporadic autism and intellectual disability. Further studies of T-box transcription factors will enhance our understanding of neurodevelopmental disorders and inform approaches to new therapies.