Publications

Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1-6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7-9. Although ICPN are anatomically diverse10-14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ([Formula: see text]) ICPN compared with secondary somatosensory cortex-projecting ([Formula: see text]) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in [Formula: see text] versus [Formula: see text] ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.

Mammalian gene clusters contain a range of CTCF binding sites. In addition to their importance in organizing a TAD border, which isolates the most posterior genes from the rest of the cluster, the positions and orientations of these sites suggest that CTCF may be instrumental in the selection of various subsets of contiguous genes, which are targets of distinct remote enhancers located in the flanking regulatory landscapes. We examined this possibility by producing an allelic series of cumulative in mutations in these sites, up to the abrogation of CTCF binding in the five sites located on one side of the TAD border. In the most impactful alleles, the global chromatin architecture of the locus was modified, yet not drastically, illustrating that CTCF sites located on one side of a strong TAD border are sufficient to organize at least part of this insulation. Spatial colinearity in the expression of these genes along the major body axis was nevertheless maintained, despite abnormal expression boundaries. In contrast, strong effects were scored in the selection of target genes responding to particular enhancers, leading to the misregulation of genes in specific structures. Altogether, while most enhancer-promoter interactions can occur in the absence of this series of CTCF sites, the binding of CTCF in the cluster is required to properly transform a rather unprecise process into a highly discriminative mechanism of interactions, which is translated into various patterns of transcription accompanied by the distinctive chromatin topology found at this locus. Our allelic series also allowed us to reveal the distinct functional contributions for CTCF sites within this cluster, some acting as insulator elements, others being necessary to anchor or stabilize enhancer-promoter interactions, and some doing both, whereas they all together contribute to the formation of a TAD border. This variety of tasks may explain the amazing evolutionary conservation in the distribution of these sites among paralogous clusters or between various vertebrates.

Domestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 BC. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture.

The cell cortex is a highly dynamic network of cytoskeletal filaments in which motor proteins induce active cortical stresses which in turn drive dynamic cellular processes such as cell motility, furrow formation or cytokinesis during cell division. Here, we develop a three-dimensional computational model of a cell cortex in the viscous limit including active cortical flows. Combining active gel and thin shell theory, we base our computational tool directly on the force balance equations for the velocity field on a discretized and arbitrarily deforming cortex. Since our method is based on the general force balance equations, it can easily be extended to more complex biological dependencies in terms of the constitutive laws or a dynamic coupling to a suspending fluid. We validate our algorithm by investigating the formation of a cleavage furrow on a biological cell immersed in a passive outer fluid, where we successfully compare our results to axi-symmetric simulations. We then apply our fully three-dimensional algorithm to fold formation and to study furrow formation under the influence of non-axisymmetric disturbances such as external shear. We report a reorientation mechanism by which the cell autonomously realigns its axis perpendicular to the furrow plane thus contributing to the robustness of cell division under realistic environmental conditions.

The Bronze Age is a complex period of social, cultural and economic changes. Recent paleogenomic studies have documented a large and rapid genetic change in early Bronze Age populations from Central Europe. However, the detailed demographic and genetic processes involved in this change are still debated. Here we have used spatially explicit simulations of genomic components to better characterize the demographic and migratory conditions that may have led to this change. We investigated various scenarios representing the expansion of pastoralists from the Pontic steppe, potentially linked to the Yamnaya cultural complex, and their interactions with local populations in Central Europe, considering various eco-evolutionary factors, such as population admixture, competition and long-distance dispersal. Our results do not support direct competition but rather the cohabitation of pastoralists and farmers in Central Europe, with limited gene flow between populations. They also suggest occasional long-distance migrations accompanying the expansion of pastoralists and a demographic decline in both populations following their initial contact. These results link recent archaeological and paleogenomic observations and move further the debate of genomic changes during the early Bronze Age.

The Antarctic coastal fauna is characterized by high endemism related to the progressive cooling of Antarctic waters and their isolation by the Antarctic Circumpolar Current. The origin of the Antarctic coastal fauna could involve either colonization from adjoining deep-sea areas or migration through the Drake Passage from sub-Antarctic areas. Here, we tested these hypotheses by comparing the morphology and genetics of benthic foraminifera collected from Antarctica, sub-Antarctic coastal settings in South Georgia, the Falkland Islands and Patagonian fjords. We analyzed four genera (Cassidulina, Globocassidulina, Cassidulinoides, Ehrenbergina) of the family Cassidulinidae that are represented by at least nine species in our samples. Focusing on the genera Globocassidulina and Cassidulinoides, our results showed that the first split between sub-Antarctic and Antarctic lineages took place during the mid-Miocene climate reorganization, probably about 20 to 17 million years ago (Ma). It was followed by a divergence between Antarctic species ~ 10 Ma, probably related to the cooling of deep water and vertical structuring of the water-column, as well as broadening and deepening of the continental shelf. The gene flow across the Drake Passage, as well as between South America and South Georgia, seems to have occurred from the Late Miocene to the Early Pliocene. It appears that climate warming during 7-5 Ma and the migration of the Polar Front breached biogeographic barriers and facilitated inter-species hybridization. The latest radiation coincided with glacial intensification (~ 2 Ma), which accelerated geographic fragmentation of populations, demographic changes, and genetic diversification in Antarctic species. Our results show that the evolution of Antarctic and sub-Antarctic coastal benthic foraminifera was linked to the tectonic and climatic history of the area, but their evolutionary response was not uniform and reflected species-specific ecological adaptations that influenced the dispersal patterns and biogeography of each species in different ways.

Erk signaling regulates cellular decisions in many biological contexts. Recently, we have reported a series of Erk activity traveling waves that coordinate regeneration of osteoblast tissue in zebrafish scales. These waves originate from a central source region, propagate as expanding rings, and impart cell growth, thus controlling tissue morphogenesis. Here, we present a minimal reaction-diffusion model for Erk activity waves. The model considers three components: Erk, a diffusible Erk activator, and an Erk inhibitor. Erk stimulates both its activator and inhibitor, forming a positive and negative feedback loop, respectively. Our model shows that this system can be excitable and propagate Erk activity waves. Waves originate from a pulsatile source that is modeled by adding a localized basal production of the activator, which turns the source region from an excitable to an oscillatory state. As Erk activity periodically rises in the source, it can trigger an excitable wave that travels across the entire tissue. Analysis of the model finds that positive feedback controls the properties of the traveling wavefront and that negative feedback controls the duration of Erk activity peak and the period of Erk activity waves. The geometrical properties of the waves facilitate constraints on the effective diffusivity of the activator, indicating that waves are an efficient mechanism to transfer growth factor signaling rapidly across a large tissue.

Various behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila melanogaster, in which only ~0.1% of the brain's neurons contain circadian clocks. Clock neurons transmit the timing information to a plethora of non-clock neurons via poorly understood mechanisms. Here, we address the molecular underpinning of this phenomenon by profiling circadian gene expression in non-clock neurons that constitute the mushroom body, the center of associative learning and sleep regulation. We show that circadian clocks drive rhythmic expression of hundreds of genes in mushroom body neurons, including the Neurofibromin 1 (Nf1) tumor suppressor gene and Pka-C1. Circadian clocks also drive calcium rhythms in mushroom body neurons via NF1-cAMP/PKA-C1 signaling, eliciting higher mushroom body activity during the day than at night, thereby promoting daytime wakefulness. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep.

Foraminifera are a primarily marine taxon widespread in all oceanic habitats, from shallow, brackish-water settings to deep-seafloor and pelagic realms. Their diversity is remarkable with several thousand species described and a fossil record tracing back to the Cambrian. While foraminifera represent one of the best-studied groups of marine meiofauna, much less is known about their non-marine relatives. The first freshwater foraminifera were described in the 19th century by European and North American protozoologists, but interest in them lapsed during much of the 20th century and was not rekindled until the advent of molecular systematics provided a fresh impetus to their study. Several new species, genera, and families have been described recently based on morphological and molecular data derived from cultured specimens. In parallel, environmental genomic studies revealed that foraminifera are highly diverse and ubiquitous in freshwater and soil environments. Molecular phylogenetic analyses places non-marine foraminifera in a few clades among the large array of single-chambered (monothalamous) lineages, suggesting that several independent colonization events of freshwater and terrestrial habitats occurred. Non-marine foraminifera are turning from obscure curiosities to being recognized as an important part of soil and freshwater microbial communities, a major component of these complex environments.

The elephant proboscis (trunk), which functions as a muscular hydrostat with a virtually infinite number of degrees of freedom, is a spectacular organ for delicate to heavy object manipulation as well as social and sensory functions. Using high-resolution motion capture and functional morphology analyses, we show here that elephants evolved strategies that reduce the biomechanical complexity of their trunk. Indeed, our behavioral experiments with objects of various shapes, sizes, and weights indicate that (1) complex behaviors emerge from the combination of a finite set of basic movements; (2) curvature, torsion, and strain provide an appropriate kinematic representation, allowing us to extract motion primitives from the trunk trajectories; (3) transport of objects involves the proximal propagation of an inward curvature front initiated at the tip; (4) the trunk can also form pseudo-joints for point-to-point motion; and (5) the trunk tip velocity obeys a power law with its path curvature, similar to human hand drawing movements. We also reveal with unprecedented precision the functional anatomy of the African and Asian elephant trunks using medical imaging and macro-scale serial sectioning, thus drawing strong connections between motion primitives and muscular synergies. Our study is the first combined quantitative analysis of the mechanical performance, kinematic strategies, and functional morphology of the largest animal muscular hydrostat on Earth. It provides data for developing innovative "soft-robotic" manipulators devoid of articulations, replicating the high compliance, flexibility, and strength of the elephant trunk. VIDEO ABSTRACT.