The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice

Abstract

Cortical expansion and folding are often linked to the evolution of higher intelligence, but molecular and cellular mechanisms underlying cortical folding remain poorly understood. The hominoid-specific gene TBC1D3 undergoes segmental duplications during hominoid evolution, but its role in brain development has not been explored. Here, we found that expression of TBC1D3 in ventricular cortical progenitors of mice via in utero electroporation caused delamination of ventricular radial glia cells (vRGs) and promoted generation of self-renewing basal progenitors with typical morphology of outer radial glia (oRG), which are most abundant in primates. Furthermore, down-regulation of TBC1D3 in cultured human brain slices decreased generation of oRGs. Interestingly, localized oRG proliferation resulting from either in utero electroporation or transgenic expression of TBC1D3, was often found to underlie cortical regions exhibiting folding. Thus, we have identified a hominoid gene that is required for oRG generation in regulating the cortical expansion and folding.DOI: http://dx.doi.org/10.7554/eLife.18197.001

High-resolution comparative analysis of great ape genomes

“…Human and chimpanzee protein-encoding changes and structural differences in regulatory DNA or in the copy number of gene families have all been implicated in adaptation (2, 3). Indeed, several potentially high-impact regulatory changes (4, 5) and human-specific genes (6–9) that are important in synapse density, neuronal count, and other morphological differences have been identified. Most of these genetic differences, however, were not initially recognized upon comparison of human and ape genomes because the genetic changes mapped to regions of rapid genomic structural change that were not resolved in draft genome assemblies.…”

Primate neocortex development and evolution: Conserved versus evolved folding

“…Thus, on the one hand, eliciting differential neuronal migration by genetic manipulations in mouse embryos has been found to suffice to induce neocortical folding in this normally lissencephalic rodent (Del Toro et al, ). On the other hand, there are several recent studies showing that increasing NPC number and proliferative capacity in mouse embryos can induce neocortical folding (Florio et al, ; Ju et al, ; Liu et al, ; Rash et al, ; Stahl et al, ; Wang et al, ). Moreover, in the neocortex of the developing ferret, a gyrencephalic mammal, NPC number and proliferation is higher in the germinal zones of a prospective gyrus than a prospective sulcus (De Juan Romero, Bruder, Tomasello, Sanz‐Anquela, & Borrell, ), and altering NPC number and proliferation in the developing ferret neocortex by genetic manipulation has been shown to affect the degree of neocortical folding (Masuda et al, ; Nonaka‐Kinoshita et al, ; Poluch & Juliano, ; Toda et al, ).…”

“…Most of these genes are known to regulate neuronal migration, pointing to neuronal migration as a major mechanism underlying neocortical folding (Fernandez et al, ; Sun & Hevner, ). The other approach is studying the effects of manipulating genes that regulate neural progenitor cell (NPC) pool sizes, neuron production and neuronal migration in a lissencephalic experimental animal, the mouse (Rash et al, ; Stahl et al, ; Florio et al, ; Ju et al, ; Wang et al, ; Del Toro et al, ; Liu et al, ), and a gyrencephalic experimental animal, the ferret (Masuda et al, ; Nonaka‐Kinoshita et al, ; Poluch & Juliano, ; Shinmyo et al, ; Toda et al, ). In addition, a recent report has linked changes in stiffness of human fetal neocortex tissue to neocortical folding in an ex vivo system, suggesting a role of biophysical parameters in the context of human neocortical folding (Long et al, ).…”

“…In fact, there is general consensus that the degree of neocortex folding has changed during mammalian, and notably primate, evolution (Kelava et al, 2013;Lewitus et al, 2014;Sun & Hevner, 2014;Zilles et al, 2013). Previous studies have addressed potential mechanisms underlying neocortical folding (Dehay, Kennedy, & Kosik, 2015;Fernandez et al, 2016;Striedter, Srinivasan, & Monuki, 2015;Sun & Hevner, 2014); these involve cellular parameters such as cell production (Florio et al, 2015;Ju et al, 2016;Liu et al, 2017;Masuda et al, 2015;Nonaka-Kinoshita et al, 2013;Rash, Tomasi, Lim, Suh, & Vaccarino, 2013;Stahl et al, 2013;Toda, Shinmyo, Dinh Duong, Masuda, & Kawasaki, 2016;Wang, Hou, & Han, 2016), cell migration (Reiner et al, 1995;Del Toro et al, 2017;Shinmyo et al, 2017), cell growth, and cell-cell interactions, with neurons as the major cell type, as well as biophysical parameters of the neocortex tissue such as stiffness (Karzbrun, † Joint first authors. Kshirsagar, Cohen, Hanna, & Reiner, 2018;Tallinen et al, 2016;Tallinen, Chung, Biggins, & Mahadevan, 2014).…”

Using brain organoids to study human neurodevelopment, evolution and disease

“…Indeed manipulation of bRG numbers in mice, by manipulating the expression of human-enriched genes or by introducing human-specific genes during development, changes the neuronal output and results in the gyrification of an otherwise smooth brain. Some of the most pronounced genes, controlling bRGs numbers, some of which later on through the change of neuronal output lead to cortical folding in mice, are the ARGAP11B, HOPX, TMEM14B, TBC1D3, TRNP1, hedgehog signaling and others Ju et al, 2016;Kelava et al, 2012;Liu et al, 2017;Narayanan et al, 2018;Stahl et al, 2013;Vaid et al, 2018;Wang, Hou, & Han, 2016). It was shown in ferrets that differences in gene expression profiles in the germinal zones of a future gyrus or sulcus control RGs function and eventually the folding pattern ( Despite the main hypothesis, which proposes bRGs as the key players in the expansion and gyrification of the cortex, it has also been proposed that the mechanical forces can influence the formation of folds.…”