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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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Spatial Organization of Neocortical Excitatory Neuron Clones(A) 3D reconstruction images of representative clones that are “cone” shaped (left) and “cylinder” shaped (right) at P7–P10 (top) and P21–P30 (bottom) labeled at E10–E12.(B) Quantification of the ratio of the maximal lateral dispersion in the superficial layer 2/3 in all dimensions (d2) to that in the deep layer 6 (d1) (see A) for clones located in different regions of the neocortex (medial [M], n = 19; dorsal [D], n = 33; lateral [L], n = 16; see inset at the bottom). Individual circles represent a single clone. Mean and SEM are shown in red (∗p < 0.05 and ∗∗p < 0.01; n.s., not significant).(C and D) No correlation between the clone shape and the clone size (C) or the ratio of neuron number in the superficial (2–4) and deep (5–6) layers (D). Each dot indicates a clone and black lines indicate mean ± SEM.See also Movies S3 and S4.
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fig6: Spatial Organization of Neocortical Excitatory Neuron Clones(A) 3D reconstruction images of representative clones that are “cone” shaped (left) and “cylinder” shaped (right) at P7–P10 (top) and P21–P30 (bottom) labeled at E10–E12.(B) Quantification of the ratio of the maximal lateral dispersion in the superficial layer 2/3 in all dimensions (d2) to that in the deep layer 6 (d1) (see A) for clones located in different regions of the neocortex (medial [M], n = 19; dorsal [D], n = 33; lateral [L], n = 16; see inset at the bottom). Individual circles represent a single clone. Mean and SEM are shown in red (∗p < 0.05 and ∗∗p < 0.01; n.s., not significant).(C and D) No correlation between the clone shape and the clone size (C) or the ratio of neuron number in the superficial (2–4) and deep (5–6) layers (D). Each dot indicates a clone and black lines indicate mean ± SEM.See also Movies S3 and S4.

Mentions: Although it has long been postulated that ontogenetic clonal units are the building blocks of the neocortex (Rakic, 1988), the precise topological organization of individual clonal units has not been determined. Our 3D reconstruction of individual clones permitted a quantitative analysis of the spatial organization of well-defined clones labeled at specific developmental stages and located in particular neocortical areas. Regardless of their size and location, all clones were organized into vertical clusters, which is consistent with a predominantly radial migration of neurons from their birthplace to the final destination (Figures 1C, 2A, 3A, and 4A). When we analyzed the clones labeled at E10–E12 that tended to be larger in size and thus offered more spatial features, we found that they exhibited distinguishable spatial organization patterns. Some clones were similarly dispersed laterally in deep and superficial layers (termed as “cylinder” shape), whereas other clones were substantially more dispersed in superficial layers than deep layers (termed as “cone” shape) (Figure 6A and Movies S3 and S4).


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)

Spatial Organization of Neocortical Excitatory Neuron Clones(A) 3D reconstruction images of representative clones that are “cone” shaped (left) and “cylinder” shaped (right) at P7–P10 (top) and P21–P30 (bottom) labeled at E10–E12.(B) Quantification of the ratio of the maximal lateral dispersion in the superficial layer 2/3 in all dimensions (d2) to that in the deep layer 6 (d1) (see A) for clones located in different regions of the neocortex (medial [M], n = 19; dorsal [D], n = 33; lateral [L], n = 16; see inset at the bottom). Individual circles represent a single clone. Mean and SEM are shown in red (∗p < 0.05 and ∗∗p < 0.01; n.s., not significant).(C and D) No correlation between the clone shape and the clone size (C) or the ratio of neuron number in the superficial (2–4) and deep (5–6) layers (D). Each dot indicates a clone and black lines indicate mean ± SEM.See also Movies S3 and S4.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4225456&req=5

fig6: Spatial Organization of Neocortical Excitatory Neuron Clones(A) 3D reconstruction images of representative clones that are “cone” shaped (left) and “cylinder” shaped (right) at P7–P10 (top) and P21–P30 (bottom) labeled at E10–E12.(B) Quantification of the ratio of the maximal lateral dispersion in the superficial layer 2/3 in all dimensions (d2) to that in the deep layer 6 (d1) (see A) for clones located in different regions of the neocortex (medial [M], n = 19; dorsal [D], n = 33; lateral [L], n = 16; see inset at the bottom). Individual circles represent a single clone. Mean and SEM are shown in red (∗p < 0.05 and ∗∗p < 0.01; n.s., not significant).(C and D) No correlation between the clone shape and the clone size (C) or the ratio of neuron number in the superficial (2–4) and deep (5–6) layers (D). Each dot indicates a clone and black lines indicate mean ± SEM.See also Movies S3 and S4.
Mentions: Although it has long been postulated that ontogenetic clonal units are the building blocks of the neocortex (Rakic, 1988), the precise topological organization of individual clonal units has not been determined. Our 3D reconstruction of individual clones permitted a quantitative analysis of the spatial organization of well-defined clones labeled at specific developmental stages and located in particular neocortical areas. Regardless of their size and location, all clones were organized into vertical clusters, which is consistent with a predominantly radial migration of neurons from their birthplace to the final destination (Figures 1C, 2A, 3A, and 4A). When we analyzed the clones labeled at E10–E12 that tended to be larger in size and thus offered more spatial features, we found that they exhibited distinguishable spatial organization patterns. Some clones were similarly dispersed laterally in deep and superficial layers (termed as “cylinder” shape), whereas other clones were substantially more dispersed in superficial layers than deep layers (termed as “cone” shape) (Figure 6A and Movies S3 and S4).

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