Human-specific ARHGAP11B induces hallmarks of neocortical expansion in developing ferret neocortex

Abstract

The evolutionary increase in size and complexity of the primate neocortex is thought to underlie the higher cognitive abilities of humans. ARHGAP11B is a human-specific gene that, based on its expression pattern in fetal human neocortex and progenitor effects in embryonic mouse neocortex, has been proposed to have a key function in the evolutionary expansion of the neocortex. Here, we study the effects of ARHGAP11B expression in the developing neocortex of the gyrencephalic ferret. In contrast to its effects in mouse, ARHGAP11B markedly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, and results in extension of the neurogenic period and an increase in upper-layer neurons. Consequently, the postnatal ferret neocortex exhibits increased neuron density in the upper cortical layers and expands in both the radial and tangential dimensions. Thus, human-specific ARHGAP11B can elicit hallmarks of neocortical expansion in the developing ferret neocortex.

Human-specificARHGAP11Bis necessary and sufficient for human-type basal progenitor levels in primate brain organoids

“…Taken together, these results indicate that the human-specific gene ARHGAP11B, similar to results previously obtained in embryonic mouse (Florio et al, 2015), embryonic ferret (Kalebic et al, 2018) and fetal marmoset (Heide et al, 2020) neocortex, can substantially increase the abundance of cycling BPs in developing cerebral cortex-like tissue of our closest living relative, the chimpanzee.…”

“…ARHGAP11B is a human-specific gene (Dennis et al, 2017;Sudmant et al, 2010) and the first such gene to have been implicated in human neocortical development and evolution Florio et al, 2016;Heide et al, 2020;Kalebic et al, 2018). In fetal human neocortex, ARHGAP11B is preferentially expressed in cNPCs (Florio et al, 2015;Florio et al, 2018).…”

“…In fetal human neocortex, ARHGAP11B is preferentially expressed in cNPCs (Florio et al, 2015;Florio et al, 2018). When 6 overexpressed in embryonic mouse and ferret neocortex, ARHGAP11B has been found to increase the proliferation and abundance of BPs (Florio et al, 2015;Kalebic et al, 2018), the cNPC class implicated in neocortical expansion during human development and evolution (Borrell & Götz, 2014;Dehay et al, 2015;Florio & Huttner, 2014;Lui et al, 2011). Moreover, a very recent study in which ARHGAP11B was expressed under the control of its own promoter to physiological levels in the fetal neocortex of the common marmoset has demonstrated that this human-specific gene can indeed induce the hallmarks of neocortical expansion in this nonhuman primate, increasing neocortex size, folding, BP levels and upper-layer neuron numbers (Heide et al, 2020).…”

Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

“…During evolution, a hominid-specific partial duplication of ARHGAP11A led to the emergence of ARHGAP11B, which has been linked to cerebral cortex expansion in humans. In the human developing cortex, ARHGAP11B is expressed in neural progenitors and its forcedexpression in developing mouse cortices, ferrets and marmosets promotes basal progenitor generation and neuron production (Florio et al, 2015;Heide et al, 2020;Kalebic et al, 2018). ARHGAP11B, however, lacks both the GTPase activity and the RNA motif for localizing to endfeet and indeed shows no subcellular localization in human cortices (Florio et al, 2018).…”

Lis1 mutation prevents basal radial glia-like cell production in the mouse

“…We hence focused on bRG-like cell production at mid-corticogenesis in Lis1 HET mouse mutants. bRG producing mechanisms have been associated with either alterations of mitosis spindle orientation leading to more oblique and vertical divisions (Kalebic et al, 2018; Liu et al, 2017; Wang et al, 2016; Wong et al, 2015), and/or to detachment from the apical surface via decreased cell adhesion (Ju et al, 2016; Martínez-Martínez et al, 2016; Narayanan et al, 2018; Tavano et al, 2018; Taverna et al, 2014). Many of the genes that were described to increase bRG-like cell generation induce more oblique divisions (Penisson et al, 2019), and mitotic spindle orientation is a well-described mechanism that may contribute to the fine tuning of aRG daughter cell fate (LaMonica et al, 2013; Taverna et al, 2014).…”