Abstract
The cortical area map is initially patterned by transcription factor (TF) gradients in the neocortical primordium, which define a "protomap" in the embryonic ventricular zone (VZ). However, mechanisms that propagate regional identity from VZ progenitors to cortical plate (CP) neurons are unknown. Here we show that the VZ, subventricular zone (SVZ), and CP contain distinct molecular maps of regional identity, reflecting different gene expression gradients in radial glia progenitors, intermediate progenitors, and projection neurons, respectively. The "intermediate map" in the SVZ is modulated by Eomes (also known as Tbr2), a T-box TF. Eomes inactivation caused rostrocaudal shifts in SVZ and CP gene expression, with loss of corticospinal axons and gain of corticotectal projections. These findings suggest that cortical areas and connections are shaped by sequential maps of regional identity, propagated by the Pax6 → Eomes → Tbr1 TF cascade. In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autistic Disorder / genetics
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Autistic Disorder / metabolism
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Autistic Disorder / pathology
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Body Patterning
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Brain Mapping
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Cerebral Cortex / anatomy & histology*
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Cerebral Cortex / growth & development
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Cerebral Cortex / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Female
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Gene Expression
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Intellectual Disability / genetics
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Intellectual Disability / metabolism
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Intellectual Disability / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Neural Pathways / cytology
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Neural Pathways / metabolism
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Neurons / cytology
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Neurons / metabolism
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PAX6 Transcription Factor
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism
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Pregnancy
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism*
Substances
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DNA-Binding Proteins
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Eomes protein, mouse
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Eye Proteins
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Homeodomain Proteins
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PAX6 Transcription Factor
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PAX6 protein, human
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Paired Box Transcription Factors
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Pax6 protein, mouse
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Repressor Proteins
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T-Box Domain Proteins
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Tbr1 protein, mouse