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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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Unitary Production of Excitatory Neurons by RGPs(A) 3D reconstruction images of representative symmetric proliferative (left) and asymmetric neurogenic (right) clones. Schematics of the clone are shown at the top. RG, radial glia; N, neuron; IP, intermediate progenitor.(B) Percentage of symmetric proliferative division versus asymmetric neurogenic division at different embryonic stages.(C) Quantification of the size of asymmetric neurogenic clones labeled at E10–E12 (n = 109).(D) Clone size distribution of the asymmetric neurogenic clones at E10–E12 fitted by a Gaussian distribution, indicating an average RGP output of ∼8–9 neurons (mean μ0 = 8.4, SD δ = 2.6; fitting error = 5.3%; blue broken line; termed “Unitary Gaussian”).(E) Gaussian fitting of the overall clone size variation. The 192 clones with a size of up to 50 neurons were fitted by the sum (black line) of a series of Gaussians centered on integer multiples of the mean of Unitary Gaussian in D (1μ0, 2μ0, 3μ0; colored lines; higher-order Gaussians are not plotted for clarity).(F) Quantification of the size of asymmetric neurogenic clones located in different neocortical areas (SS, 7.9 ± 0.3, n = 44; MO, 8.1 ± 0.7, n = 10; AUD, 7.3 ± 0.6, n = 15; VISal, 9.0 ± 1.0, n = 2; PTLp, 8.8 ± 0.7, n = 5; Medial, 7.6 ± 1.2, n = 10). SS, somatosensory cortex; MO, motor cortex; AUD, auditory cortex; VISal, visual cortex; PTLp, posterior parietal association areas; Medial, including anterior cingulate area, dorsal peduncular area, infralimbic area, prelimbic area, and retrosplenial area.Data are presented as mean ± SEM. n.s., not significant. See also Figures S3 and S4.
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fig2: Unitary Production of Excitatory Neurons by RGPs(A) 3D reconstruction images of representative symmetric proliferative (left) and asymmetric neurogenic (right) clones. Schematics of the clone are shown at the top. RG, radial glia; N, neuron; IP, intermediate progenitor.(B) Percentage of symmetric proliferative division versus asymmetric neurogenic division at different embryonic stages.(C) Quantification of the size of asymmetric neurogenic clones labeled at E10–E12 (n = 109).(D) Clone size distribution of the asymmetric neurogenic clones at E10–E12 fitted by a Gaussian distribution, indicating an average RGP output of ∼8–9 neurons (mean μ0 = 8.4, SD δ = 2.6; fitting error = 5.3%; blue broken line; termed “Unitary Gaussian”).(E) Gaussian fitting of the overall clone size variation. The 192 clones with a size of up to 50 neurons were fitted by the sum (black line) of a series of Gaussians centered on integer multiples of the mean of Unitary Gaussian in D (1μ0, 2μ0, 3μ0; colored lines; higher-order Gaussians are not plotted for clarity).(F) Quantification of the size of asymmetric neurogenic clones located in different neocortical areas (SS, 7.9 ± 0.3, n = 44; MO, 8.1 ± 0.7, n = 10; AUD, 7.3 ± 0.6, n = 15; VISal, 9.0 ± 1.0, n = 2; PTLp, 8.8 ± 0.7, n = 5; Medial, 7.6 ± 1.2, n = 10). SS, somatosensory cortex; MO, motor cortex; AUD, auditory cortex; VISal, visual cortex; PTLp, posterior parietal association areas; Medial, including anterior cingulate area, dorsal peduncular area, infralimbic area, prelimbic area, and retrosplenial area.Data are presented as mean ± SEM. n.s., not significant. See also Figures S3 and S4.

Mentions: Previous work has suggested that, during early neocortical development, RGPs divide either symmetrically to amplify their number or asymmetrically to produce neurons while self-renewing (Florio and Huttner, 2014). MADM clonal analysis validated these observations. We found that G2-X clones could be grouped into two types. They either contained sizable numbers of both green and red neurons (more than three neurons of each color) distributed throughout the superficial and deep layers (termed type I, Figure 2A, left) or else contained a “majority” population in one color and a “minority” population (less than four neurons, mostly one or two neurons) in the other color (termed type II, Figure 2A, right). Interestingly, in type II clones, the minority population always resided in the deeper layers relative to the majority population. Consistent with the “inside-out” sequence of neocortical neurogenesis (Angevine and Sidman, 1961), the minority population thus represents the earliest-born neurons in the labeled lineage. Moreover, the relative scarcity of the minority population indicates that the original daughter cell, from which the minority population arises, is either a neuron or an IP capable of undergoing only one to two rounds of division (i.e., producing no more than four neuronal progeny) (Noctor et al., 2004), whereas the majority population originates from a self-renewing RGP. Therefore, type II clones represent asymmetric neurogenic clones (Figure 2A, right, top). In contrast, type I clones represent symmetric proliferative clones, as the two originally labeled daughter cells are most probably self-renewing RGPs, each capable of producing a large cohort of neuronal progeny (Figure 2A, left, top).


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)

Unitary Production of Excitatory Neurons by RGPs(A) 3D reconstruction images of representative symmetric proliferative (left) and asymmetric neurogenic (right) clones. Schematics of the clone are shown at the top. RG, radial glia; N, neuron; IP, intermediate progenitor.(B) Percentage of symmetric proliferative division versus asymmetric neurogenic division at different embryonic stages.(C) Quantification of the size of asymmetric neurogenic clones labeled at E10–E12 (n = 109).(D) Clone size distribution of the asymmetric neurogenic clones at E10–E12 fitted by a Gaussian distribution, indicating an average RGP output of ∼8–9 neurons (mean μ0 = 8.4, SD δ = 2.6; fitting error = 5.3%; blue broken line; termed “Unitary Gaussian”).(E) Gaussian fitting of the overall clone size variation. The 192 clones with a size of up to 50 neurons were fitted by the sum (black line) of a series of Gaussians centered on integer multiples of the mean of Unitary Gaussian in D (1μ0, 2μ0, 3μ0; colored lines; higher-order Gaussians are not plotted for clarity).(F) Quantification of the size of asymmetric neurogenic clones located in different neocortical areas (SS, 7.9 ± 0.3, n = 44; MO, 8.1 ± 0.7, n = 10; AUD, 7.3 ± 0.6, n = 15; VISal, 9.0 ± 1.0, n = 2; PTLp, 8.8 ± 0.7, n = 5; Medial, 7.6 ± 1.2, n = 10). SS, somatosensory cortex; MO, motor cortex; AUD, auditory cortex; VISal, visual cortex; PTLp, posterior parietal association areas; Medial, including anterior cingulate area, dorsal peduncular area, infralimbic area, prelimbic area, and retrosplenial area.Data are presented as mean ± SEM. n.s., not significant. See also Figures S3 and S4.
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fig2: Unitary Production of Excitatory Neurons by RGPs(A) 3D reconstruction images of representative symmetric proliferative (left) and asymmetric neurogenic (right) clones. Schematics of the clone are shown at the top. RG, radial glia; N, neuron; IP, intermediate progenitor.(B) Percentage of symmetric proliferative division versus asymmetric neurogenic division at different embryonic stages.(C) Quantification of the size of asymmetric neurogenic clones labeled at E10–E12 (n = 109).(D) Clone size distribution of the asymmetric neurogenic clones at E10–E12 fitted by a Gaussian distribution, indicating an average RGP output of ∼8–9 neurons (mean μ0 = 8.4, SD δ = 2.6; fitting error = 5.3%; blue broken line; termed “Unitary Gaussian”).(E) Gaussian fitting of the overall clone size variation. The 192 clones with a size of up to 50 neurons were fitted by the sum (black line) of a series of Gaussians centered on integer multiples of the mean of Unitary Gaussian in D (1μ0, 2μ0, 3μ0; colored lines; higher-order Gaussians are not plotted for clarity).(F) Quantification of the size of asymmetric neurogenic clones located in different neocortical areas (SS, 7.9 ± 0.3, n = 44; MO, 8.1 ± 0.7, n = 10; AUD, 7.3 ± 0.6, n = 15; VISal, 9.0 ± 1.0, n = 2; PTLp, 8.8 ± 0.7, n = 5; Medial, 7.6 ± 1.2, n = 10). SS, somatosensory cortex; MO, motor cortex; AUD, auditory cortex; VISal, visual cortex; PTLp, posterior parietal association areas; Medial, including anterior cingulate area, dorsal peduncular area, infralimbic area, prelimbic area, and retrosplenial area.Data are presented as mean ± SEM. n.s., not significant. See also Figures S3 and S4.
Mentions: Previous work has suggested that, during early neocortical development, RGPs divide either symmetrically to amplify their number or asymmetrically to produce neurons while self-renewing (Florio and Huttner, 2014). MADM clonal analysis validated these observations. We found that G2-X clones could be grouped into two types. They either contained sizable numbers of both green and red neurons (more than three neurons of each color) distributed throughout the superficial and deep layers (termed type I, Figure 2A, left) or else contained a “majority” population in one color and a “minority” population (less than four neurons, mostly one or two neurons) in the other color (termed type II, Figure 2A, right). Interestingly, in type II clones, the minority population always resided in the deeper layers relative to the majority population. Consistent with the “inside-out” sequence of neocortical neurogenesis (Angevine and Sidman, 1961), the minority population thus represents the earliest-born neurons in the labeled lineage. Moreover, the relative scarcity of the minority population indicates that the original daughter cell, from which the minority population arises, is either a neuron or an IP capable of undergoing only one to two rounds of division (i.e., producing no more than four neuronal progeny) (Noctor et al., 2004), whereas the majority population originates from a self-renewing RGP. Therefore, type II clones represent asymmetric neurogenic clones (Figure 2A, right, top). In contrast, type I clones represent symmetric proliferative clones, as the two originally labeled daughter cells are most probably self-renewing RGPs, each capable of producing a large cohort of neuronal progeny (Figure 2A, left, top).

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