2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe cerebral cortex is the integrative and executive center of the mammalian CNS, making up over three-quarters of the human brain (). An increase in neuronal number, and thus cerebral cortex size, is thought to provide a template for more complex neural architectures, contributing to differences in cognitive abilities between humans and other primates (, ). The developmental mechanisms that generate differences in neuronal number and diversity, and thus cerebral cortex size in humans, other primates, and mammals in general, are currently poorly understood.During embryonic development, all excitatory cortical projection neurons are generated directly or indirectly from neuroepithelial progenitor cells of the cortical ventricular zone (VZ) (). A common feature of cerebral cortex development in all mammals is that multipotent cortical progenitor cells produce multicellular clones of neurons over developmental time, generating different classes of cortical projection neurons and then glial cells in fixed temporal order (, , , ). Neuroepithelial cells are the founder progenitor cell population in the cerebral cortex, giving rise to neurogenic radial glial cells (RGCs) that generate all of the excitatory neurons of the cerebral cortex, either directly or indirectly (, ). RGCs can self-renew (proliferate), directly generate postmitotic neurons, or produce two different types of neurogenic progenitor cells: intermediate/basal progenitor cells (IPCs) and outer RGCs (oRGCs) (, , , ). Both basal progenitor cells and oRGCs can also self-renew or generate neurons, with some evidence that IPCs have limited proliferative capacity (, href="#bib36" rid="bib36" class=" bibr popnode">Rakic, 2000).Although several different processes have been proposed to contribute to increased neuronal numbers in the primate cortex (href="#bib14" rid="bib14" class=" bibr popnode">Herculano-Houzel, 2009), research has focused on two primary mechanisms: an increase in the number of founder neuroepithelial cells, driven by increased proliferation of neuroepithelial cells before entering the neurogenic period of cortical development (href="#bib9" rid="bib9" class=" bibr popnode">Florio and Huttner, 2014, href="#bib12" rid="bib12" class=" bibr popnode">Geschwind and Rakic, 2013), and an increase in the number of oRGCs, as found in primates (href="#bib13" rid="bib13" class=" bibr popnode">Hansen et al., 2010). The latter in turn amplify the output of RGCs (for a recent review, see href="#bib5" rid="bib5" class=" bibr popnode">Dehay et al., 2015). The radial unit hypothesis proposes that an increase in the number of founder neuroepithelial cells is the basis for the increase in cortical size in humans compared with other primates (href="#bib12" rid="bib12" class=" bibr popnode">Geschwind and Rakic, 2013, href="#bib36" rid="bib36" class=" bibr popnode">Rakic, 2000). The identification of oRGCs in primates and other mammals has led to a modification of the radial unit hypothesis to suggest that the addition of oRGCs effectively increases the progenitor population and thus is a major contributor to primate cortical expansion (href="#bib8" rid="bib8" class=" bibr popnode">Fietz et al., 2010, href="#bib13" rid="bib13" class=" bibr popnode">Hansen et al., 2010, href="#bib39" rid="bib39" class=" bibr popnode">Smart et al., 2002).Current models for the cellular mechanisms that generate the increased numbers of neurons found in the primate cerebral cortex rely on extrapolating from a large body of work on rodent, primarily mouse, cortical neurogenesis. However, the cortex of humans and other primates appears to follow different scaling rules than that of other mammals, including mouse, in terms of the relationship between cortical volume and cell number and overall body size (href="#bib1" rid="bib1" class=" bibr popnode">Azevedo et al., 2009). We and others have developed human stem cell systems to study cerebral cortex neurogenesis in vitro (href="#bib7" rid="bib7" class=" bibr popnode">Espuny-Camacho et al., 2013, href="#bib25" rid="bib25" class=" bibr popnode">Mariani et al., 2012, href="#bib37" rid="bib37" class=" bibr popnode">Shi et al., 2012a), finding that directed differentiation of human pluripotent stem cells (PSCs) to cerebral cortex progenitor cells robustly replays the temporal order of cortical neurogenesis, including the production of the diversity of progenitor cell types found in vivo (href="#bib37" rid="bib37" class=" bibr popnode">Shi et al., 2012a).In this study, we extended the use of stem cell systems to compare human, macaque, and chimpanzee cortical neurogenesis to understand the developmental mechanisms regulating increased cortical size in different primates. We find that there are several important differences in cerebral cortex progenitor cell biology between rodents and primates, and between humans and nonhuman primates, that contribute to the marked differences in neuronal number among the different species. Together, these findings constitute multiple new insights into the biology of generating large brains in relatively slowly developing mammals, including primates.