Cell Biology seminars

The basis of the mind, of mental states, and complex behaviors is the flow of energy through microscopic and macroscopic brain structures. Energy flow through brain circuits is powered by thousands of mitochondria populating the inside of every neuron, glial, and other nucleated cell across the brain-body unit. This seminar will cover emerging approaches to study the mind-mitochondria connection and present early attempts to map the distribution and diversity of mitochondria across brain tissue. In rodents, I will present convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct behaviorally-relevant mitochondrial phenotypes exist across large-scale mouse brain networks. Extending these findings to the human brain, I will present a developing systematic biochemical and molecular map of mitochondrial variation across cortical and subcortical brain structures, representing a foundation to understand the origin of complex energy patterns that give rise to the human mind.

We are interested in the biology of macrophages, which represent the first line of defense against pathogens. In Drosophila, the embryonic hemocytes arise from the mesoderm whereas glial cells arise from multipotent precursors in the neurogenic region. These cell types represent, respectively, the macrophages located outside and within the nervous system (similar to vertebrate microglia). Thus, despite their different origin, hemocytes and glia display common functions. In addition, both cell types express the Glide/Gcm transcription factor, which plays an evolutionarily conserved role as an anti-inflammatory factor. Moreover, embryonic hemocytes play an evolutionarily conserved and fundamental role in development. The ability to migrate and to contact different tissues/organs most likely allow macrophages to function as signaling hubs. The function of macrophages beyond the recognition of the non-self calls for revisiting the biology of these heterogeneous and plastic cells in physiological and pathological conditions across evolution.

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding, both of which emerge during development. Over the last few years, work from my lab has shown that specific cellular and genetic mechanisms play central roles in cortex folding, particularly linked to neural stem and progenitor cells. Key mechanisms include high rates of neurogenesis, high abundance of basal Radial Glia Cells (bRGCs), and neuron migration, all of which are intertwined during development. We have also shown that primary cortical folds follow highly stereotyped patterns, defined by a spatial-temporal protomap of gene expression within germinal layers of the developing cortex. I will present recent findings from my laboratory revealing novel cellular and genetic mechanisms that regulate cortex expansion and folding. We have uncovered the contribution of epigenetic regulation to the establishment of the cortex folding protomap, modulating the expression levels of key transcription factors that control progenitor cell proliferation and cortex folding. At the single cell level, we have identified an unprecedented diversity of cortical progenitor cell classes in the ferret and human embryonic cortex. These are differentially enriched in gyrus versus sulcus regions and establish parallel cell lineages, not observed in mouse. Our findings show that genetic and epigenetic mechanisms in gyrencephalic species diversify cortical progenitor cell types and implement parallel cell linages, driving the expansion of neurogenesis and patterning cerebral cortex folds.

In the fourth of this year’s Brain Prize webinars, Mike Fainzilber (Weizmann Institute of Science, Israel), Yingxi Lin (UT Southwestern, USA), and Richard Tsien (New York University, USA) will present their work on synapse to nucleus signalling. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by two of the winners of the 2023 Brain Prize, Michael Greenberg and Erin Schuman.

Astrocytes are multifunctional glial cells, implicated in neurogenesis and synaptogenesis, supporting and fine-tuning neuronal activity and maintaining brain homeostasis by controlling blood-brain barrier permeability. During the last years a number of studies have shown that astrocytes can also be converted into neurons if they force-express neurogenic transcription factors or miRNAs. Direct astrocytic reprogramming to induced-neurons (iNs) is a powerful approach for manipulating cell fate, as it takes advantage of the intrinsic neural stem cell (NSC) potential of brain resident reactive astrocytes. To this end, astrocytic cell fate conversion to iNs has been well-established in vitro and in vivo using combinations of transcription factors (TFs) or chemical cocktails. Challenging the expression of lineage-specific TFs is accompanied by changes in the expression of miRNAs, that post-transcriptionally modulate high numbers of neurogenesis-promoting factors and have therefore been introduced, supplementary or alternatively to TFs, to instruct direct neuronal reprogramming. The neurogenic miRNA miR-124 has been employed in direct reprogramming protocols supplementary to neurogenic TFs and other miRNAs to enhance direct neurogenic conversion by suppressing multiple non-neuronal targets. In our group we aimed to investigate whether miR-124 is sufficient to drive direct reprogramming of astrocytes to induced-neurons (iNs) on its own both in vitro and in vivo and elucidate its independent mechanism of reprogramming action. Our in vitro data indicate that miR-124 is a potent driver of the reprogramming switch of astrocytes towards an immature neuronal fate. Elucidation of the molecular pathways being triggered by miR-124 by RNA-seq analysis revealed that miR-124 is sufficient to instruct reprogramming of cortical astrocytes to immature induced-neurons (iNs) in vitro by down-regulating genes with important regulatory roles in astrocytic function. Among these, the RNA binding protein Zfp36l1, implicated in ARE-mediated mRNA decay, was found to be a direct target of miR-124, that be its turn targets neuronal-specific proteins participating in cortical development, which get de-repressed in miR-124-iNs. Furthermore, miR-124 is potent to guide direct neuronal reprogramming of reactive astrocytes to iNs of cortical identity following cortical trauma, a novel finding confirming its robust reprogramming action within the cortical microenvironment under neuroinflammatory conditions. In parallel to their reprogramming properties, astrocytes also participate in the maintenance of blood-brain barrier integrity, which ensures the physiological functioning of the central nervous system and gets affected contributing to the pathology of several neurodegenerative diseases. To study in real time the dynamic physical interactions of astrocytes with brain vasculature under homeostatic and pathological conditions, we performed 2-photon brain intravital imaging in a mouse model of systemic neuroinflammation, known to trigger astrogliosis and microgliosis and to evoke changes in astrocytic contact with brain vasculature. Our in vivo findings indicate that following neuroinflammation the endfeet of activated perivascular astrocytes lose their close proximity and physiological cross-talk with vasculature, however this event is at compensated by the cross-talk of astrocytes with activated microglia, safeguarding blood vessel coverage and maintenance of blood-brain integrity.

In the second of this year’s Brain Prize webinars, Rob Singer (Einstein Medical College, USA), Florence Besse (Institut de Biologie Valrose, France) and Jennifer Lippincott-Schwartz (Janelia Farm Research Campus, USA) will present their work on mRNA transport, trafficking, and localization. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by the winners of the 2023 Brain Prize, Michael Greenberg, Erin Schuman and Christine Holt.

The adult intestine is a major barrier epithelium and coordinator of multi-organ functions. Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How these signals integrate to control intestinal and whole-body homeostasis is largely unknown. Addressing this gap in knowledge is central to an improved understanding of intestinal pathophysiology and its systemic consequences. Combining Drosophila and mammalian model systems my laboratory has discovered fundamental mechanisms driving intestinal regeneration and tumourigenesis and outlined complex inter-organ signaling regulating health and disease. During my talk, I will discuss inter-related areas of research from my lab, including:1- Interactions between the intestine and its microenvironment influencing intestinal regeneration and tumourigenesis. 2- Long-range signals from the intestine impacting whole-body in health and disease.

Microglia are the brain macrophages, eliciting multifaceted functions to maintain brain homeostasis across lifetime. To achieve this, microglia are able to sense a plethora of signals in their close environment. In the lab, we investigate the effect of nutrients on microglia function for several reasons: 1) Microglia express all the cellular machinery required to sense nutrients; 2) Eating habits have changed considerably over the last century, towards diets rich in fats and sugars; 3) This so-called "Western diet" is accompanied by an increase in the occurrence of neuropathologies, in which microglia are known to play a role. In my talk, I will present data showing how variations in nutrient intake alter microglia function, including exacerbation of synaptic pruning, with profound consequences for neuronal activity and behavior. I will also show unpublished data on the mechanisms underlying the effects of nutrients on microglia, notably through the regulation of their metabolic activity.

In 2023, Michael Greenberg (Harvard, USA), Erin Schuman (Max Planck Institute for Brain Research, Germany) and Christine Holt (University of Cambridge, UK) were awarded The Brain Prize for their pioneering work on activity-dependent gene transcription and local mRNA translation. In this webinar, all 3 Brain Prize winners will present their work. Each speaker will present for 25 minutes and the webinar will conclude with an open discussion. The webinar will be moderated by Kelsey Martin from the Simons Foundation.

Microglia are the resident CNS macrophages of the brain parenchyma. They have many and opposing roles in health and disease, ranging from inflammatory to anti-inflammatory and protective functions, depending on the developmental stage and the disease context. In Multiple Sclerosis, microglia are involved to important hallmarks of the disease, such as inflammation, demyelination, axonal damage and remyelination, however the exact mechanisms controlling their transformation towards a protective or devastating phenotype during the disease progression remains largely unknown until now. We wish to understand how brain microglia respond to demyelinating insults and how their behaviour changes in recovery. To do so we developed a novel histopathological analysis approach in 3D and a cell-based analysis tool that when applied in the cuprizone model of demyelination revealed region- and disease- dependent changes in microglial dynamics in the brain grey matter during demyelination and remyelination. We now use similar approaches with the aim to unravel sensitive changes in microglial dynamics during neuroinflammation in the EAE model. Furthermore, we employ constitutive knockout and tamoxifen-inducible gene-targeting approaches, immunological techniques, genetics and bioinformatics and currently seek to clarify the specific role of the brain resident microglial NF-κB molecular pathway versus other tissue macrophages in EAE.