Topic: Profilin

Defining profilin function in mammalian actin dynamics and cell behaviour

Klemens Rottner (Helmholtz Centre for Infection Research, Braunschweig) presents evidence that profilin acts as a master regulator of actin filament dynamics essential for cell migration and growth, controlling both formin- and Arp2/3 complex-dependent actin assembly pathways.

Towards Human Systems Biology of Sleep/Wake Cycles: Phosphorylation Hypothesis of Sleep

The field of human biology faces three major technological challenges. Firstly, the causation problem is difficult to address in humans compared to model animals. Secondly, the complexity problem arises due to the lack of a comprehensive cell atlas for the human body, despite its cellular composition. Lastly, the heterogeneity problem arises from significant variations in both genetic and environmental factors among individuals. To tackle these challenges, we have developed innovative approaches. These include 1) mammalian next-generation genetics, such as Triple CRISPR for knockout (KO) mice and ES mice for knock-in (KI) mice, which enables causation studies without traditional breeding methods; 2) whole-body/brain cell profiling techniques, such as CUBIC, to unravel the complexity of cellular composition; and 3) accurate and user-friendly technologies for measuring sleep and awake states, exemplified by ACCEL, to facilitate the monitoring of fundamental brain states in real-world settings and thus address heterogeneity in human.

Metabolic Remodelling in the Developing Forebrain in Health and Disease

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Motivated by the identification of autism-associated mutations in SLC7A5, a transporter for metabolically essential large neutral amino acids (LNAAs), we utilized metabolomic profiling to investigate the metabolic states of the cerebral cortex across various developmental stages. Our findings reveal significant metabolic restructuring occurring in the forebrain throughout development, with specific groups of metabolites exhibiting stage-specific changes. Through the manipulation of Slc7a5 expression in neural cells, we discovered an interconnected relationship between the metabolism of LNAAs and lipids within the cortex. Neuronal deletion of Slc7a5 influences the postnatal metabolic state, resulting in a shift in lipid metabolism and a cell-type-specific modification in neuronal activity patterns. This ultimately gives rise to enduring circuit dysfunction.

Sampling the environment with body-brain rhythms

Since Darwin, comparative research has shown that most animals share basic timing capacities, such as the ability to process temporal regularities and produce rhythmic behaviors. What seems to be more exclusive, however, are the capacities to generate temporal predictions and to display anticipatory behavior at salient time points. These abilities are associated with subcortical structures like basal ganglia (BG) and cerebellum (CE), which are more developed in humans as compared to nonhuman animals. In the first research line, we investigated the basic capacities to extract temporal regularities from the acoustic environment and produce temporal predictions. We did so by adopting a comparative and translational approach, thus making use of a unique EEG dataset including 2 macaque monkeys, 20 healthy young, 11 healthy old participants and 22 stroke patients, 11 with focal lesions in the BG and 11 in the CE. In the second research line, we holistically explore the functional relevance of body-brain physiological interactions in human behavior. Thus, a series of planned studies investigate the functional mechanisms by which body signals (e.g., respiratory and cardiac rhythms) interact with and modulate neurocognitive functions from rest and sleep states to action and perception. This project supports the effort towards individual profiling: are individuals’ timing capacities (e.g., rhythm perception and production), and general behavior (e.g., individual walking and speaking rates) influenced / shaped by body-brain interactions?

Epigenome regulation in neocortex expansion and generation of neuronal subtypes

Evolutionarily, the expansion of the human neocortex accounts for many of the unique cognitive abilities of humans. This expansion appears to reflect the increased proliferative potential of basal progenitors (BPs) in mammalian evolution. Further cortical progenitors generate both glutamatergic excitatory neurons (ENs) and GABAergic inhibitory interneurons (INs) in human cortex, whereas they produce exclusively ENs in rodents. The increased proliferative capacity and neuronal subtype generation of cortical progenitors in mammalian evolution may have evolved through epigenetic alterations. However, whether or how the epigenome in cortical progenitors differs between humans and other species is unknown. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in amplification, neuronal subtype generation and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Furthermore, we found that the elevated H3 acetylation activates expression of IN genes in in developing mouse cortex and promote proliferation of IN progenitor-like cells in cortex of Pax6 mutant mouse models. Mechanistically, H3K9ac drives the BP amplification and proliferation of these IN progenitor-like cells by increasing expression of the evolutionarily regulated gene, TRNP1. Our findings demonstrate a previously unknown mechanism that controls neocortex expansion and generation of neuronal subtypes. Keywords: Cortical development, neurogenesis, basal progenitors, cortical size, gyrification, excitatory neuron, inhibitory interneuron, epigenetic profiling, epigenetic regulation, H3 acetylation, H3K9ac, TRNP1, PAX6

At the nexus of genes, aging and environment: Understanding transcriptomic and epigenomic regulation in Parkinson's disease

Parkinson’s Disease (PD), the most common neurodegenerative movement disorder, is based on a complex interplay between genetic predispositions, aging processes, and environmental influences. In order to better understand the gene-environment axis in PD, we pursue a multi-omics approach to comprehensively interrogate genome-wide changes in histone modifications, DNA methylation, and hydroxymethylation, accompanied by transcriptomic profiling in cell and animal models of PD as well as large patient cohorts. Furthermore, we assess the plasticity of epigenomic modifications under influence of environmental factors using longitudinal cohorts of sporadic PD cases as well as mouse models exposed to specific environmental factors. Here, we present gene expression changes in PD mouse models in context of aging as well as environmental enrichment and high-fat diet.

Mechanisms underlying detection and temporal sensitivity of single-photon responses in the mammalian retina

We have long known that rod and cone signals interact within the retina and can even contribute to color vision, but the extent of these influences has remained unclear. New results with more powerful methods of RNA expression profiling, specific cell labeling, and single-cell recording have provided greater clarity and are showing that rod and cone signals can mix at virtually every level of signal processing. These interactions influence the integration of retinal signals and make an important contribution to visual perception.

The retrotrapezoid nucleus: an integrative and interoceptive hub in neural control of breathing

In this presentation, we will discuss the cellular and molecular properties of the retrotrapezoid nucleus (RTN), an integrative and interoceptive control node for the respiratory motor system. We will present the molecular profiling that has allowed definitive identification of a cluster of tonically active neurons that provide a requisite drive to the respiratory central pattern generator (CPG) and other pre-motor neurons. We will discuss the ionic basis for steady pacemaker-like firing, including by a large subthreshold oscillation; and for neuromodulatory influences on RTN activity, including by arousal state-dependent neurotransmitters and CO2/H+. The CO2/H+-dependent modulation of RTN excitability represents the sensory component of a homeostatic system by which the brain regulates breathing to maintain blood gases and tissue pH; it relies on two intrinsic molecular proton detectors, both a proton-activated G protein-coupled receptor (GPR4) and a proton-inhibited background K+ channel (TASK-2). We will also discuss downstream neurotransmitter signaling to the respiratory CPG, focusing especially on a newly-identified peptidergic modulation of the preBötzinger complex that becomes activated following birth and the initiation of air breathing. Finally, we will suggest how the cellular and molecular properties of RTN neurons identified in rodent models may contribute to understanding human respiratory disorders, such as congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS).

Cellular-resolution gene expression profiling in the neonatal marmoset brain reveals dynamic species- and region-specific differences

Molecular Biology of the Fragile X Syndrome

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wild-type tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes, and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrates that loss of FMRP alters the deployment of this histone mark. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.

Microenvironment role in axonal regeneration- looking beyond the neurons

After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow during embryonic development and after an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. This study has uncovered a previously unknown role for SGC in nerve regeneration and defined SGC as transcriptionally distinct from Schwann cells while sharing similarities with astrocytes. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Through repurposing fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, we were able to rescue the impaired regeneration in mice lacking Fasn in SGC. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.