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Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, Streicher C, Papusheva E, Insolera R, Chugh K, Kodish O, Huang K, Simons BD, Luo L, Hippenmeyer S, Shi SH - Cell (2014)

Bottom Line: We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner.Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size.These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.

ABSTRACT
Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ?8-9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ?1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

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Individual RGPs Produce Both Deep- and Superficial-Layer Excitatory Neurons(A) 3D reconstruction images of representative clones labeled at different embryonic stages. Note that all clones contain both superficial (2–4) and deep (5–6) layer neurons.(B) Confocal images of an E10 clone stained with the antibodies against EGFP (green), tdTomato (red), BRN2 (white), and CTIP2 (cyan) and with DAPI (blue). High-magnification images of representative superficial (B’) and deep (B’’) layer neurons (broken lines) are shown at the bottom. Arrows indicate neurons positive for BRN2, arrowheads indicate neurons positive for CTIP2, and open arrowheads indicate neurons negative for BRN2 or CTIP2. Scale bars, 100 μm and 25 μm.(C) Percentage of clones containing both superficial and deep-layer neurons versus those containing only superficial- or deep-layer neurons.(D) Percentage of neurons in the clones located in superficial or deep layers.See also Figure S5.
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fig4: Individual RGPs Produce Both Deep- and Superficial-Layer Excitatory Neurons(A) 3D reconstruction images of representative clones labeled at different embryonic stages. Note that all clones contain both superficial (2–4) and deep (5–6) layer neurons.(B) Confocal images of an E10 clone stained with the antibodies against EGFP (green), tdTomato (red), BRN2 (white), and CTIP2 (cyan) and with DAPI (blue). High-magnification images of representative superficial (B’) and deep (B’’) layer neurons (broken lines) are shown at the bottom. Arrows indicate neurons positive for BRN2, arrowheads indicate neurons positive for CTIP2, and open arrowheads indicate neurons negative for BRN2 or CTIP2. Scale bars, 100 μm and 25 μm.(C) Percentage of clones containing both superficial and deep-layer neurons versus those containing only superficial- or deep-layer neurons.(D) Percentage of neurons in the clones located in superficial or deep layers.See also Figure S5.

Mentions: A recent study suggested that RGPs are fate restricted to selectively produce only superficial- or deep-layer neurons (Franco et al., 2012). We found that, regardless of the time of labeling and clone size, the vast majority of clones spanned both the deep (5–6) and superficial (2–4) layers (Figure 4A). Besides the assessment of spatial localization, we also performed immunohistochemical analysis using antibodies against well-established layer-specific neuronal markers (Greig et al., 2013; Kwan et al., 2012). BRN2 or CUX1 (superficial layer marker)- and CTIP2 (deep layer marker) -positive neurons were found to coexist in individual clones (Figures 4B and S5). We also observed subplate neurons (SPNs) in clones labeled at E10–E11, which were grouped with other deep-layer neurons (Figures S2C and S2D).


Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, Streicher C, Papusheva E, Insolera R, Chugh K, Kodish O, Huang K, Simons BD, Luo L, Hippenmeyer S, Shi SH - Cell (2014)

Individual RGPs Produce Both Deep- and Superficial-Layer Excitatory Neurons(A) 3D reconstruction images of representative clones labeled at different embryonic stages. Note that all clones contain both superficial (2–4) and deep (5–6) layer neurons.(B) Confocal images of an E10 clone stained with the antibodies against EGFP (green), tdTomato (red), BRN2 (white), and CTIP2 (cyan) and with DAPI (blue). High-magnification images of representative superficial (B’) and deep (B’’) layer neurons (broken lines) are shown at the bottom. Arrows indicate neurons positive for BRN2, arrowheads indicate neurons positive for CTIP2, and open arrowheads indicate neurons negative for BRN2 or CTIP2. Scale bars, 100 μm and 25 μm.(C) Percentage of clones containing both superficial and deep-layer neurons versus those containing only superficial- or deep-layer neurons.(D) Percentage of neurons in the clones located in superficial or deep layers.See also Figure S5.
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fig4: Individual RGPs Produce Both Deep- and Superficial-Layer Excitatory Neurons(A) 3D reconstruction images of representative clones labeled at different embryonic stages. Note that all clones contain both superficial (2–4) and deep (5–6) layer neurons.(B) Confocal images of an E10 clone stained with the antibodies against EGFP (green), tdTomato (red), BRN2 (white), and CTIP2 (cyan) and with DAPI (blue). High-magnification images of representative superficial (B’) and deep (B’’) layer neurons (broken lines) are shown at the bottom. Arrows indicate neurons positive for BRN2, arrowheads indicate neurons positive for CTIP2, and open arrowheads indicate neurons negative for BRN2 or CTIP2. Scale bars, 100 μm and 25 μm.(C) Percentage of clones containing both superficial and deep-layer neurons versus those containing only superficial- or deep-layer neurons.(D) Percentage of neurons in the clones located in superficial or deep layers.See also Figure S5.
Mentions: A recent study suggested that RGPs are fate restricted to selectively produce only superficial- or deep-layer neurons (Franco et al., 2012). We found that, regardless of the time of labeling and clone size, the vast majority of clones spanned both the deep (5–6) and superficial (2–4) layers (Figure 4A). Besides the assessment of spatial localization, we also performed immunohistochemical analysis using antibodies against well-established layer-specific neuronal markers (Greig et al., 2013; Kwan et al., 2012). BRN2 or CUX1 (superficial layer marker)- and CTIP2 (deep layer marker) -positive neurons were found to coexist in individual clones (Figures 4B and S5). We also observed subplate neurons (SPNs) in clones labeled at E10–E11, which were grouped with other deep-layer neurons (Figures S2C and S2D).

Bottom Line: We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner.Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size.These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.

ABSTRACT
Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ?8-9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ?1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

Show MeSH
Related in: MedlinePlus