Detlev Arendt, Victor Borrel Franco, Thomas Bourgeron, Jean-François Brunet, Alain Chédotal (organiser), Colette Dehay, Sonia Garel, Genevieve Konopka, Arnold Kriegstein, Ed Lein, Stephen Noctor, Alessandra Pierani, Franck Polleux (organiser), Jonathan Pritchard, Molly Przeworski, Qiu Zilong , Linda Richards, John Rubenstein, Dietmar Schmucker, Debra (Debby) Silver, Pierre Vanderhaeghen
And Héloïse Dufour (Cercle FSER) & Claude Tran (Educavox) pour the “Scientific meeting open to the public)
by Alain Chédotal and Franck Polleux
16 – 21 October, 2017
The objective of this meeting entitled ‘The genetic basis of human traits and behaviors’, held from October 16th to 21st at the Fondation des Treilles, was to discuss recent advances in our understanding of the genetic, cellular and molecular mechanisms underlying brain evolution. This is a topic of intense research using a wide range of approaches and model and non-model organisms including recently humans. The central question is to understand how genomic evolution shapes species-specific aspects of brain development and function. In particular, almost half of the presentations were dealing with the central questions: What makes the human brain specific? What are the genomic and developmental changes that allowed the emergence of human cognitive abilities during recent evolution? During the meeting we addressed the following topics: The evolution of neural circuits, in particular commissural and visceral, and their genetic determinants in invertebrates and vertebrates. The genetic factors controlling cortical evolution (size, complexity, cortical areas…). Neurodevelopmental disorders and related diseases (schizophrenia, autism spectrum disorders, callosal dysgenesis). Single cell genomic insights into human brain development and evolution. Role of microglial cells and Cajal Retzius cells in the development and evolution of the neocortex.
Keywords: evolution, brain, neurons, genetics, development
The abstracts of the talks are reproduced below in the order of their presentation at the workshop.
Arnold Kriegstein (UC San Francisco, CA, USA) presented his analysis of some of the cellular and molecular aspects of the development characterizing primates and in particular human cortex. He focused on his discovery of outer radial glial (oRG) cells which are neural progenitors participating to the expansion of the number of neurons populating superficial layers of the cortex in human. He also reported some new efforts to perform single cell RNA sequencing in order to analyze the diversity of cell types within progenitors of the human cortex. His work identified novel genes and unique signaling pathways expressed in various sub-populations of neural progenitors, migrating and differentiating neurons as well as non-neuronal cell types in the developing human brain.
Ed Lein (Allen Brain Institute, Seattle, USA) presented some new results from a large scale study of neuronal diversity characterizing developing human cortical neurons using an array of approaches including multiplexed patch clamp recording and single cell RNA sequencing. His work reveals novel neuronal subtypes defined by their functional properties, their connectivity (or at least their morphology) and their gene expression profiles. This large-scale approaches will lead to new insights into what is unique about cortical circuits characterizing the human brain.
Colette Dehay (INSERM, Lyon) discussed the spatiotemporal regulation of the cell cycle in the neocortex how corticogenesis dynamics differs between primates and rodents. She described the results of a miRNA profiling of the cortex germinal zone which showed that there are distinct signatures in the outer and inner subventricular zone and that about one half of the differentially expressed miRNAs are primate specific. She also provided evidence supporting a laminar and area specific dynamics of radial migration.
Franck Polleux (Columbia University, New York, USA) presented some new results on the function of SRGAP2A and its human-specific gene duplication SRGAP2C during cortical circuit development. His results demonstrate that SRGAP2A co-regulate the maturation and density of both excitatory and inhibitory synaptic development in cortical pyramidal neurons. Humanization of SRGAP2C expression, which binds to and inhibits SRGAP2A functions, leads to formation of more excitatory and inhibitory synapses onto cortical PNs. Rabies monosynaptic tracing experiments demonstrate that the increased number of excitatory connections made onto layer 2/3 PNs originate specifically from increased number of cortico-cortical feedback projections. Finally, he presented some new experimental approaches based on in vivo 2-photon microscopy in awake behaving mice aimed at probing the functional consequences of these changes in structural connectivity on circuit function.
Pierre Vanderhaeghen (ULB, Belgium), presented his ongoing work on brain evolution and how this is driven by regulatory mutations, coding mutations and gene duplications. He showed that about 400 genes are hominid specific and some are involved in corticogenesis and presented data on their expression dynamics taking human-specific gene duplication affecting Notch2 as an example. He reported that there a 5 Notch2-like genes in humans called Notch2NL and tested their function using human-iPSCs differentiation into cortical neural progenitors. He also showed that the generation of human/mouse chimeric cortex by transplantation, reveals species specific patterns of neuronal differentiation. His results suggest that the emergence of Notch2NL gene duplications in the human genome participated to the expansion of the neural progenitor pool and therefore to expansion of the cortex characterizing humans.
Zilong Qiu (Shanghai Neuroscience Institute, China), presented some new results aimed at generating genetically-modified primate models. Numerous limitations exist in using mouse as a model for the study of complex traits characterizing the human brain especially its development which is far more complex. Several groups throughout the world are attempting to generate genetically-modified primate models which might be more appropriate to study complex aspects of circuit development and function especially in the context of neurodevelopmental disease models such as autism. His group recently generated the first macaque model of a form of Rett-like syndrome due to duplication of the gene MeCP2. His group successfully generated multiple individual macaques carrying duplications of MeCP2 and his results show that these individuals display phenotypes partially recapitulating some aspects of development and behaviors characterizing the human patients including reduced sociability and anxiety. He also discussed efforts to generate more primate models and also development of imaging methods aimed at tracking longitudinal aspects of brain development and behavior in these primates.
Molly Przeworski (Columbia University, New York, USA) presented an overview of what we have learned about the dynamics of human adaptation at the genomic level and in particular the evidence against adaptations often being due to single changes of large effect. She discussed recent work from her lab that identified loci under viability selection in contemporary humans by analyzing large biomedical data sets.
Jonathan Pritchard (Stanford University, USA) spoke about emerging evidence that heritable variation in quantitative traits is due to many loci of small effects scattered throughout the genome, and often maps outside the core processes thought to relate to the trait. He then presented results from his lab about recent human adaptations due to small shifts in allele frequencies at many loci scattered throughout the genome.
Thomas Bourgeron (Pasteur Institute, Paris) discussed his work on the identification of the genomic architecture of autism spectrum disorders. His results demonstrate the complexity of this genomic architecture ranging from penetrant, rare monogenic loss-of-function mutations or copy-number variations to the majority of cases where many (10 to hundreds) of mutations in coding regions or other genomic alterations affecting non-coding regulatory regions might combine their effects to lead to ASD phenotypes. He also presented an original web-based interface that concatenate many sources of information on genomics, transcriptomics, proteomics of genes associated with ASD that should facilitate their functional analysis.
Victor Borell (Alicante, Spain), exposed a new model explaining the expansion of cortical size in Amniotes based on a comparison of progenitor cell division and cell cycle length in the olfactory bulb and neocortex. The involvement of Slit/Robo and Delta signaling pathways was presented.
Stephen Noctor (UC Davis, CA, USA) presented some detailed analysis of the spatial and temporal pattern of development and differentiation of microglial cells in the primate and human cortex. Using comparative analysis with other mammalian species such as rodents, carnivores and birds, he argued that the abundance, timing and complexity of microglial cell differentiation presents some primate-specific aspects that might participate to primate-specific features of cortical development.
Alessandra Pierani (IJM, Paris), discussed the embryonic origin of Cajal Retzius cells which are transient and moving organizers of cortical patterning. She focused on the Dbx1 transcription factor which plays a key role in the specification of Cajal Retzius cells. Interestingly, there are primate-specific upstream sequences in the Dbx1 locus. Dbx1 is also expressed in the subplate in human fetuses. Last she shows that preventing Cajal Retzius cell death using genetic tools severely perturbs cortical development.
Debra Silver (Duke University, NC-USA) spoke about the role of human-accelerated regions (HAR) which are human-specific changes in non-coding, regulatory regions of the genome which can alter pattern of genes expression and therefore specific aspects of brain development. She talked about a specific HAR called HAR5 located in an enhancer of Frizzled8, a regulator of Wnt signaling. Using a transgenic mouse reporter approach, she demonstrated that HAR5 enhancer alters the pattern of Frz8 expression in the forebrain and results in cortical expansion. She extended these approach to other HARs and her lab is currently analyzing the evolutionary and developmental impact of some of these HARs on brain patterning. Finally, she also reported some functional analysis of the exon junction complex (EJC) which is an RNA binding complex implicated in many stages of the RNA life cycle, including splicing, translation, decay, and RNA localization. She presented some new results following up on previously discovered haploinsufficiency for the EJC protein, Magoh, and how it results in microcephaly, due to defects in neural progenitor proliferation and neuronal apoptosis.
Sonia Garel (ENS, Paris), summarized her work on the assembly of cortical circuits and the species-specific differences in the organization of thalamo-cortical projections (TCA). She showed that corridor cells, which guide thalamo-cortical axons are present in birds, reptiles and mammals, but that their positioning differs between species. She also addressed the question of the maintenance of neuronal circuits during brain growth and showed that a reallocation of Cajal Retzius cells from a transient reservoir sustains neocortex construction. She also presented her studies on microglia and how these sexually dimorphic cells influence brain development.
Geneviève Konopka (UT Southwestern, TX, USA), presented her approach to study the impact of human-specific gene expression signatures on specific signaling pathways relevant to brain development. Using a comparative genomics approach, she identified genes that have been modified in the human brain and their function is then further examined using both human neuronal cultures and animal models. She presented some results on a gene expression ‘module’ regulated by a novel transcriptional role for the transcription factor CLOCK in human neurons. Her results support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function.
Dietmar Schmucker (VIB Leuven, Belgium) presented some new mechanisms regulating axon branching and synaptogenesis during brain development. Using a single sensory neuron in Drosophila that project to the central nervous system where it grows and branches in a stereotypic manner, He performed a screen to identify novel genes regulating specific aspects of axon development. His work reveals a novel PI3-kinase signaling pathway that regulates branch-specific features of synaptic development.
Linda Richards (Queensland Brain Institute, Brisbane, Australia), took example of the corpus callosum (CC) to illustrate how axonal wiring relates to brain function. CC is only present in placental mammals, but there are also homotopic commissural connections in a marsupial model, the fat-tailed Dunnart. CC malformations are very frequent (1:3000 births), and there are also abnormal contralateral targeting disorders. She discussed the link between abnormal CC wiring and cognitive function and if genetic diagnosis (such as DCC mutations) has a prognostic value.
John Rubenstein (UC San Francisco, California, USA) presented his approach to map the regulatory genomic mechanisms underlying the control of gene expression by transcription factors patterning the developing brain. His results demonstrate that the complex temporal and spatial dynamics of gene expression regulated by a transcription factor such as the Dlx gene family results from the combined action of transcription factor binding site, long range enhancers and chromatin remodeling. His work reveals some of the genomic mechanisms that evolution is acting on in order to modify brain development and patterning by altering spatial and temporal dynamics of gene expression in a species-specific manner.
Alain Chédotal (Institut de la Vision, Paris), presented his work on the development, function and evolution of commissural circuits in bilateria. His data suggest that axon guidance mechanisms are less conserved than originally thought and that mutations in some receptors (such as Robo3) or receptor losses (such as Dcc in some birds) might have contributed to the evolution of brain circuits and the acquisition of new behaviors.
Detlev Arendt (EMBL, Heidelberg, Germany), discussed his research on the cell type as an evolutionary unit and the notion of apomorphy. A cell type such as the ciliary photoreceptors, is a set of differentiated cells that uses the same partitioning of the genome. He also presented his single cell transcriptomic analysis of sponge cell types. Cnidarians have a nerve net and mechanosensory neurons. He discussed the evolution of mediolateral patterning and the chimeric brain hypothesis.
Jean François Brunet (ENS, Paris), talked about the development and evolution of the visceral nervous system and the role of the master gene Phox2b in its specification. He took examples in rodents, human, fish and ascidian.