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

• Published in: Nature (London) Vol. 515; no. 7526; pp. 264 - 268
• Main Authors: Lui, Jan H., Nowakowski, Tomasz J., Pollen, Alex A., Javaherian, Ashkan, Kriegstein, Arnold R., Oldham, Michael C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.11.2014; Nature Publishing Group
• Subjects: 13/1; 13/51; 14/19; 14/34; 14/63; 38; 45/61; 45/90; 45/91; 631/378/2571/2579; 64/60; Analysis; Animals; Cell Cycle; Cell Proliferation; Gene expression; Gene Expression Profiling; Humanities and Social Sciences; Humans; letter; Lymphokines - genetics; Lymphokines - metabolism; Mice; multidisciplinary; Neocortex; Neocortex - cytology; Neocortex - growth & development; Neocortex - metabolism; Neuroglia; Neuroglia - cytology; Neuroglia - metabolism; Platelet-derived growth factor; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - metabolism; Receptor, Platelet-Derived Growth Factor beta - metabolism; Science; Signal Transduction - genetics; Transcription, Genetic; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature13973

The transcriptional profiles of radial glia are compared between humans and mice during neurogenesis, implicating the growth factor PDGFD and its receptor, PDGFRβ, in human but not mouse neocortical development. A genetic link to human neocortical expansion The unique intellectual capabilities of humans are widely attributed to the expansion of the human neocortex in comparison to primates and other mammals. Recent reports implicated the elevated proliferative potential of radial glia, a type of neuronal precursor cell than spans the developing cerebral cortex, as a driver for neocortical expansion. Arnold Kriegstein and colleagues take this concept further by identifying evolutionary changes in radial glia gene expression that may have contributed to human neocortical expansion. They find that humans and mice exhibit highly conserved gene expression patterns amongst radial glia except for a few specific signalling pathways. PDGFD and its receptor, PDGFRβ, show distinct expression patterns and profiles in human cortex development that are absent in mice. Disrupting these paths in human brain slice cultures prevents normal cell cycle progression, whereas ectopic activation of these paths in mice enhances radial glia proliferation and dispersion, revealing one critical mechanism specific to human cortical development. Evolutionary expansion of the human neocortex underlies many of our unique mental abilities. This expansion has been attributed to the increased proliferative potential 1 , 2 of radial glia (RG; neural stem cells) and their subventricular dispersion from the periventricular niche 3 , 4 , 5 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 6 , 7 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.