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Title: The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice}
Article:
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.
Introduction:
It is generally assumed that the expansion of the mammalian neocortex during evolution correlates with the increase in intelligence, and this process involves increased production of cortical neurons, resulting from an extended neurogenic period as well as increased proliferative ability of neural stem cells and progenitors( Geschwind and Rakic, 2013; Lui et al., 2011; Sun and Hevner, 2014; Zilles et al., 2013). To fit into a limited cranium, expanded cortical surfaces are folded to form gyri and sulci. Recent cross-species studies have shown the emergence of an outer subventricular zone( OSVZ) in the primate cortex, consisting of a massive pool of proliferating basal progenitors( BPs) and post-mitotic neurons( Betizeau et al., 2013; Fietz et al., 2010; Hansen et al., 2010; Reillo et al., 2011; Smart et al., 2002). Unlike the neuroepithelia-derived ventricular radial glial cells, which undergo repeated and typically asymmetric cell division at the apical surface of the ventricular zone, the BPs, after delamination from the apical surface, translocate to the SVZ, where they exhibit symmetric or asymmetric divisions. In primates, the recently identified outer( basal) radial glia( referred to as oRG or bRG) and the intermediate progenitors( IPs) in the OSVZ, which can undergo multiple rounds of symmetric or asymmetric divisions( Betizeau et al., 2013; Hansen et al., 2010), are two major forms of BPs. By contrast, the IPs and minimal oRG cells in the mouse SVZ usually exhibit final division to generate a pair of post-mitotic neurons( Shitamukai et al., 2011; Wang et al., 2011). The radial and lateral expansion of BPs is thought to be a main cause of cortical folding of gyrencephalic species( Fietz and Huttner, 2011; Fietz et al., 2010; Hansen et al., 2010; Lewitus et al., 2014; Lui et al., 2011; Reillo et al., 2011). In support of this hypothesis, forced expansion of BPs by down-regulating the DNA-associated protein Trnp1 or overexpressing cell cycle regulatory proteins Cdk4/Cyclin D1 resulted in gyrification of the cerebral cortex in naturally lissencephalic mouse or gyrencephalic ferret( Nonaka-Kinoshita et al., 2013; Stahl et al., 2013). Given that genetic differences between humans and other species are likely to be the causes of human-specific traits, including complexity of cortical morphology, extensive studies have been performed in comparing genes and genetic elements of different species of primates and mammals( Arcila et al., 2014; Fietz et al., 2012; Florio et al., 2015; Johnson et al., 2009, 2015; Kang et al., 2011; Konopka et al., 2012; Lui et al., 2014; Miller et al., 2014; O'Bleness et al., 2012). In particular, several recent studies have aimed to uncover the distinctive transcriptional signature of the expanded human OSVZ or BPs that reside there, leading to the identification of a group of genes highly expressed in the human OSVZ( Miller et al., 2014), and human-specific orthologs preferentially expressed in human RGs( Florio et al., 2015; Lui et al., 2014; Miller et al., 2014; Pollen et al., 2015; Thomsen et al., 2016). For examples, platelet-derived growth factor D is expressed specifically and functionally important in human but not mouse RGs( Lui et al., 2014). A human lineage-specific Rho GTPase-activating protein could enhance the generation of IPs and cause neocortex expansion when expressed in the mouse brain( Florio et al., 2015). Since cortical folding emerges progressively during primate evolution, multiple primate- and hominid-specific genes are likely to be involved in the emergence of cortical folding. Gene duplication may play critical roles in brain evolution( Geschwind and Rakic, 2013). In particular, duplication of specific genes in humans may be responsible for the marked increase in cortical folding. The TBC1D3 gene is derived from a segmental duplication, with multiple copies present in the human chromosome 17 and present in the chimpanzee genome as a single copy gene( but absent in other species)( Hodzic et al., 2006; Pei et al., 2002; Perry et al., 2008; Zody et al., 2006). Indeed, TBC1D3 corresponds to one of the core duplicons that have been implicated in the expansion of intrachromosomal segmental duplications during hominoid evolution( Jiang et al., 2007). Because the timing of origination and amplification of the TBC1D3 gene is consistent with the evolutionary divergence of primates( Perry et al., 2008; Stahl and Wainszelbaum, 2009), we decided to explore its role in brain development by expressing this gene in mice. We found TBC1D3 expression markedly elevated the generation and proliferation of BPs and resulted in extensive cortex folding in the mouse brain, and further delineated the molecular and cellular mechanisms underlying its action. Furthermore, TBC1D3 is essential for the generation of BPs in cultured developing human brain slices. The transgenic mice generated in this study may provide a feasible model to link cortical folding to higher brain functions.
Discussion:
In this study, we found a remarkable effect of the hominoid-specific gene TBC1D3 in promoting the generation of oRG cells in mice with a high proliferative ability previously observed in primates. Importantly, this oRG generation is accompanied by the appearance of cortical folding. Furthermore, we elucidated the cellular mechanisms underlying the generation of proliferative oRG cells by showing that TBC1D3 expresssion caused increased delamination of VZ neuroprogenitors via down-regulation of N-cadherin, and elevated proliferative ability of BPs is accompanied by a reduced expression of Trnp1 and likely involves Ras-ERK signaling cascade. These effects together resulted in the expansion and dispersion of BPs, giving rise to increased number of newborn neurons and leading to cortical folding( for model see Figure 7J). In small rodents, RGs in the VZ and IPs in the SVZ are two major cell types responsible for cortex development. However, amplification of VZ progenitors via overexpression of β-catenin in the mouse brain led to the folding of the ventricular rather than cortical surface( Chenn and Walsh, 2002), and amplification of IPs only increased the brain size without inducing cortical folding in mice( Nonaka-Kinoshita et al., 2013). Recent studies have established the association between the relative abundance of oRG and the degree of cortical folding in various species( Betizeau et al., 2013; Hansen et al., 2010; Reillo et al., 2011; Shitamukai et al., 2011; Wang et al., 2011). In the present study, we showed that increased population of oRG in mice is accompanied with cortical fold formation, supporting the critical role of highly proliferative oRG in cortical expansion and gyrification in primates. It is postulated that oRG cells are derived from the ventricular RGs, presumably requiring delamination from apical anchoring( Borrell and Gotz, 2014). However, loss of adherens junction proteins or breaking their linkage to the cytoskeletal belts by down-regulating the small GTPase RhoA( Cappello et al., 2012; Lien et al., 2006) had little effect on oRG generation or cortical folding, although apically anchored progenitor cells became delaminated. Thus, delamination of VZ progenitors is not sufficient for generating highly proliferative BPs, and changes in cell cycle regulatory factors are also be required. In the present study, we showed that expression of TBC1D3 led to not only down-regulation of N-cadherin, leading to VZ progenitor delamination, but also reduced Trnp1 expression and enhanced ERK signaling that could be involved in elevated proliferation of delaminated cells. Furthermore, other functions of TBC1D3 may also contribute to the cortical folding phenotype we observed. For examples, cell culture studies of TBC1D3 have suggested its potential role in membrane endocytosis, as well as Ras activation and epidermal growth factor receptor( EGFR) signaling( Wainszelbaum et al., 2008), processes that may be involved in various aspects of neural development leading to cortical folding and gyrification. Indeed, we found that Ras activity was involved in TBC1D3-induced proliferation of BPs. Recent single-cell transcriptome analyses of human oRG cells have identified multiple preferentially expressed genes related to extracellular matrix formation, cell migration, and stemness, including the most specific oRG marker HOPX( Pollen et al., 2015; Thomsen et al., 2016). Strikingly, many HOPX positive cells were observed in TBC1D3 TG mice. The relationship between TBC1D3 expression and these oRG markers remains to be clarified. Simple ectopic localization of RG cells outside of the ventricular zone may not be sufficient to cause cortical expansion or folding as shown in a previous study( Yoon et al., 2014). Appearance of oRG-like features, including the contact with pia surface by the basal process, multiple rounds of cell division, expression of specific markers, as well as clustered regional distribution of BPs observed in this study, may play prominent roles in cortical folding. Cortical expansion is assumed to be associated with the emergence of uniquely cognitive skills in primates( Luders et al., 2008; Zilles et al., 2013). However, this hypothesis has been mainly based on across species comparative studies. Global or regional-specific changes in gyrification index( GI) have been observed in brains of subjects following various types of extensive training( Amunts et al., 1997; Luders et al., 2012; Luders et al., 2008). For example, in keyboard players, the local GI increases in response to early onset of professional training and duration of practice, and correlates with motor performance( Amunts et al., 1997). Conversely, a significant decline in the cortical GI was observed in patients with mental disorders( Bonnici et al., 2007; Wolosin et al., 2009). Understanding of the precise contribution of cortical expansion and gyrification to cognition functions has been challenging due to the lack of appropriate animal model systems. The deliberate behavior analyses for TG mice generated in this work may provide a link between cortex expansion and higher brain functions. Recently, a human-specific gene ARHGAP11B has been shown to promote production of basal IPs and cause cortical folding in the electroporated mouse brain( Florio et al., 2015). We propose that TBC1D3, which appeared earlier than ARHGAP11B during human evolution( Florio et al., 2015; Hodzic et al., 2006; Perry et al., 2008), acts as a candidate gene that controls many other genes involved in cortex expansion and folding. Multiple genes underlying different or shared cellular processes associated with neurogenesis may all contribute in part to the formation of cortical folding and gyrification found in primates. Thus, it would be of great interest to elucidate gene expression networks related with TBC1D3 expression. Identification of the ‘hub’ genes of such networks may further clarify the role of TBC1D3 in the cytoarchitectural development on the cortex. This study provides proof-of-concept that the brain development can be regulated by duplicated genes during hominoid evolution.
The outer layer of the mammalian brain the cerebral cortex plays a key role in memory , attention , awareness and thought . While rodents have a smooth cortical surface , the cortex of larger mammals such as primates is organized into folds and furrows . These folds increase the amount of cortex that can fit inside the confines of the skull , and are thought to have allowed the evolution of more advanced thought processes . Mutations in various genes are likely to have contributed to the expansion and folding of the cortex . These mutations may not always have involved changes in the instructions encoded within the genes , but might instead have involved changes in the number of copies of a gene . One plausible candidate gene is TBC1D3 , which is only found in the great apes and is active in the cortex . The chimpanzee genome contains a single copy of TBC1D3 whereas the human genome contains multiple copies . Ju , Hou et al . have now shown that introducing the TBC1D3 gene into mouse embryos triggers changes in the embryonic cortex . Specifically , this gene increases the number of a type of cell called the outer radial glial cell in the cortex . These cells give rise to new neurons , and are usually rare in mice but abundant in the brains of animals with a folded cortex . Additional experiments using samples of human brain tissue confirmed that TBC1D3 is required for the outer radial glial cells to form . The samples were collected from miscarried fetuses with the informed consent of the patients and following approved protocols and ethical guidelines . Finally , introducing the TBC1D3 gene into the mouse genome also gave rise to animals with a folded cortex , rather than their usual smooth brain surface . Further work is now required to identify how TBC1D3 helps to generate outer radial glial cells , and to work out how these cells cause the cortex to expand . Testing the behavior of mice with the TBC1D3 gene could also uncover the links between cortical folding and thought processes .