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Radial glia require PDGFD-PDGFRβ signalling in human but not mouse neocortex.

Lui JH, Nowakowski TJ, Pollen AA, Javaherian A, Kriegstein AR, Oldham MC - Nature (2014)

Bottom Line: Evolutionary expansion of the human neocortex underlies many of our unique mental abilities.However, whether or how RG gene expression varies between humans and other species is unknown.These findings highlight the requirement of PDGFD-PDGFRβ signalling for human neocortical development and suggest that local production of growth factors by RG supports the expanded germinal region and progenitor heterogeneity of species with large brains.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA.

ABSTRACT
Evolutionary expansion of the human neocortex underlies many of our unique mental abilities. This expansion has been attributed to the increased proliferative potential of radial glia (RG; neural stem cells) and their subventricular dispersion from the periventricular niche during neocortical development. Such adaptations may have evolved through gene expression changes in RG. However, whether or how RG gene expression varies between humans and other species is unknown. Here we show that the transcriptional profiles of human and mouse neocortical RG are broadly conserved during neurogenesis, yet diverge for specific signalling pathways. By analysing differential gene co-expression relationships between the species, we demonstrate that the growth factor PDGFD is specifically expressed by RG in human, but not mouse, corticogenesis. We also show that the expression domain of PDGFRβ, the cognate receptor for PDGFD, is evolutionarily divergent, with high expression in the germinal region of dorsal human neocortex but not in the mouse. Pharmacological inhibition of PDGFD-PDGFRβ signalling in slice culture prevents normal cell cycle progression of neocortical RG in human, but not mouse. Conversely, injection of recombinant PDGFD or ectopic expression of constitutively active PDGFRβ in developing mouse neocortex increases the proportion of RG and their subventricular dispersion. These findings highlight the requirement of PDGFD-PDGFRβ signalling for human neocortical development and suggest that local production of growth factors by RG supports the expanded germinal region and progenitor heterogeneity of species with large brains.

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Pdgfrβ is strongly expressed by ventral RG and weakly expressed by lateral RG in miceIn situ hybridization of Pdgfrβ in sagittal sections through the mouse forebrain (E14.5) across a medial-lateral axis (Eurexpress21: http://www.eurexpress.org/ee/) demonstrates progenitor expression in the ventral germinal regions. This expression extends into the dorsal cortex in the lateral aspect of the brain, but is not widespread. In contrast, no progenitor expression is detected in dorsomedial cortex (scale bar 500 μm, inset scale bar 100 μm). Expression is also detected in the pia and vascular pericytes. VZ: ventricular zone, SVZ: subventricular zone.
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Figure 8: Pdgfrβ is strongly expressed by ventral RG and weakly expressed by lateral RG in miceIn situ hybridization of Pdgfrβ in sagittal sections through the mouse forebrain (E14.5) across a medial-lateral axis (Eurexpress21: http://www.eurexpress.org/ee/) demonstrates progenitor expression in the ventral germinal regions. This expression extends into the dorsal cortex in the lateral aspect of the brain, but is not widespread. In contrast, no progenitor expression is detected in dorsomedial cortex (scale bar 500 μm, inset scale bar 100 μm). Expression is also detected in the pia and vascular pericytes. VZ: ventricular zone, SVZ: subventricular zone.

Mentions: The effects of PDGFD are specifically mediated by the PDGFRß receptor, which upon phosphorylation can trigger signaling pathways that promote cell proliferation6, 7, 20. Although PDGFRβ did not meet the same stringent criteria as PDGFD, its location on the DS/DE plot was proximal to PDGFD (Fig. 2d', red square), also suggesting species differences in PDGFRβ expression. Compared to genes with the highest , PDGFRβ expression was moderately correlated in human, but not mouse (Fig. 3e-f). Immunostaining for PDGFRß in GW14.5 human brain revealed strong expression throughout the telencephalic germinal zones (VZ/SVZ) and in vascular pericytes, with highest levels in dorsolateral cortical progenitors and the lateral ganglionic eminence (LGE) (Fig. 3g). In contrast, immunostaining for PDGFRß in E15.5 mouse brain revealed expression in LGE progenitors but no evidence of expression in cortical progenitors (Fig. 3h). However, we did observe very low levels of Pdgfrβ transcript in the VZ of lateral mouse cortex21 (Extended Data Fig. 8), leaving open the possibility of modest, region-specific function. Collectively, these results indicate that expression patterns of PDGFD and PDGFRß in developing neocortex have diverged considerably during human and mouse evolution, despite retaining amino-acid sequences that are ∼85% identical between the species.


Radial glia require PDGFD-PDGFRβ signalling in human but not mouse neocortex.

Lui JH, Nowakowski TJ, Pollen AA, Javaherian A, Kriegstein AR, Oldham MC - Nature (2014)

Pdgfrβ is strongly expressed by ventral RG and weakly expressed by lateral RG in miceIn situ hybridization of Pdgfrβ in sagittal sections through the mouse forebrain (E14.5) across a medial-lateral axis (Eurexpress21: http://www.eurexpress.org/ee/) demonstrates progenitor expression in the ventral germinal regions. This expression extends into the dorsal cortex in the lateral aspect of the brain, but is not widespread. In contrast, no progenitor expression is detected in dorsomedial cortex (scale bar 500 μm, inset scale bar 100 μm). Expression is also detected in the pia and vascular pericytes. VZ: ventricular zone, SVZ: subventricular zone.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4231536&req=5

Figure 8: Pdgfrβ is strongly expressed by ventral RG and weakly expressed by lateral RG in miceIn situ hybridization of Pdgfrβ in sagittal sections through the mouse forebrain (E14.5) across a medial-lateral axis (Eurexpress21: http://www.eurexpress.org/ee/) demonstrates progenitor expression in the ventral germinal regions. This expression extends into the dorsal cortex in the lateral aspect of the brain, but is not widespread. In contrast, no progenitor expression is detected in dorsomedial cortex (scale bar 500 μm, inset scale bar 100 μm). Expression is also detected in the pia and vascular pericytes. VZ: ventricular zone, SVZ: subventricular zone.
Mentions: The effects of PDGFD are specifically mediated by the PDGFRß receptor, which upon phosphorylation can trigger signaling pathways that promote cell proliferation6, 7, 20. Although PDGFRβ did not meet the same stringent criteria as PDGFD, its location on the DS/DE plot was proximal to PDGFD (Fig. 2d', red square), also suggesting species differences in PDGFRβ expression. Compared to genes with the highest , PDGFRβ expression was moderately correlated in human, but not mouse (Fig. 3e-f). Immunostaining for PDGFRß in GW14.5 human brain revealed strong expression throughout the telencephalic germinal zones (VZ/SVZ) and in vascular pericytes, with highest levels in dorsolateral cortical progenitors and the lateral ganglionic eminence (LGE) (Fig. 3g). In contrast, immunostaining for PDGFRß in E15.5 mouse brain revealed expression in LGE progenitors but no evidence of expression in cortical progenitors (Fig. 3h). However, we did observe very low levels of Pdgfrβ transcript in the VZ of lateral mouse cortex21 (Extended Data Fig. 8), leaving open the possibility of modest, region-specific function. Collectively, these results indicate that expression patterns of PDGFD and PDGFRß in developing neocortex have diverged considerably during human and mouse evolution, despite retaining amino-acid sequences that are ∼85% identical between the species.

Bottom Line: Evolutionary expansion of the human neocortex underlies many of our unique mental abilities.However, whether or how RG gene expression varies between humans and other species is unknown.These findings highlight the requirement of PDGFD-PDGFRβ signalling for human neocortical development and suggest that local production of growth factors by RG supports the expanded germinal region and progenitor heterogeneity of species with large brains.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA.

ABSTRACT
Evolutionary expansion of the human neocortex underlies many of our unique mental abilities. This expansion has been attributed to the increased proliferative potential of radial glia (RG; neural stem cells) and their subventricular dispersion from the periventricular niche during neocortical development. Such adaptations may have evolved through gene expression changes in RG. However, whether or how RG gene expression varies between humans and other species is unknown. Here we show that the transcriptional profiles of human and mouse neocortical RG are broadly conserved during neurogenesis, yet diverge for specific signalling pathways. By analysing differential gene co-expression relationships between the species, we demonstrate that the growth factor PDGFD is specifically expressed by RG in human, but not mouse, corticogenesis. We also show that the expression domain of PDGFRβ, the cognate receptor for PDGFD, is evolutionarily divergent, with high expression in the germinal region of dorsal human neocortex but not in the mouse. Pharmacological inhibition of PDGFD-PDGFRβ signalling in slice culture prevents normal cell cycle progression of neocortical RG in human, but not mouse. Conversely, injection of recombinant PDGFD or ectopic expression of constitutively active PDGFRβ in developing mouse neocortex increases the proportion of RG and their subventricular dispersion. These findings highlight the requirement of PDGFD-PDGFRβ signalling for human neocortical development and suggest that local production of growth factors by RG supports the expanded germinal region and progenitor heterogeneity of species with large brains.

Show MeSH
Related in: MedlinePlus