Nr2f1-dependent regulation of Mitochondrial Function in Neural Development and Disease
2023-2026 | Bando PRIN 2022 – MUR
Silvia De Marchis (PI NICO)
PI – PARTNER
Ivan Conte, Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Napoli, Italia
Giuseppe Lupo, Dipartimento di Biologia e Biotecnologie “C. Darwin”, Università degli Studi di Roma “La Sapienza”, Roma, Italia
Valerio Licursi, Istituto di Biologia e Patologia Molecolare (IBPM-CNR), Consiglio Nazionale delle Ricerche (CNR), Roma, Italia
Mitochondria are essential for maintaining neural cell function and are dynamically regulated during brain development. While mitochondrial regulation is known to be critical for neurogenesis, the molecular mechanisms controlling mitochondrial dynamics in neural stem/progenitor cells (NSPCs) and neurons remain poorly understood. Our previous work identified the transcription factor Nr2f1 as a key regulator of adult hippocampal neurogenesis and we recently revealed that Nr2f1 directly influences genes encoding mitochondrial proteins and regulates its function. These findings are particularly relevant to Boonstra-Bosch-Schaff optic atrophy syndrome (BBSOAS)—a rare neurodevelopmental disorder caused by mutations in NR2F1, associated with optic nerve atrophy, intellectual disability, and autistic traits, all consistent with mitochondrial dysfunction in the brain. This project aims to: identify Nr2f1-regulated transcriptional and biological pathways in NSPCs and neurons using genome-wide profiling; define the impact of Nr2f1 on mitochondrial function and its role in the maturation and plasticity of adult-born hippocampal neurons in mice; develop and utilize new Medaka fish models to study the pathophysiology and potential treatments for BBSOAS. The project aims to identify novel biomarkers and therapeutic targets for BBSOAS and related neurodevelopmental disorders involving mitochondrial impairment.
The role of miR-211 in neuronal aging: From Disease Mechanisms to Therapy
2023-2026 | Bando PRIN-PNRR 2022 – MUR
Silvia De Marchis (PI NICO)
PI – PARTNER
Ivan Conte, Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Napoli, Italia
Giuseppe Lupo, Dipartimento di Biologia e Biotecnologie “C. Darwin”, Università degli Studi di Roma “La Sapienza”, Roma, Italia
Valerio Licursi, Istituto di Biologia e Patologia Molecolare (IBPM-CNR), Consiglio Nazionale delle Ricerche (CNR), Roma, Italia
Alzheimer’s disease (AD) is the leading cause of dementia. It is characterised by the accumulation of amyloid plaques and neurofibrillary tangles, as well as progressive neurodegeneration and cognitive decline. One of the key cellular processes affected by ageing and AD is the degradation of damaged proteins, primarily via the ubiquitin-proteasome system and autophagy, both of which become impaired with age. Our project focuses on microRNA 211 (miR-211), which has recently been identified as a critical regulator of neuronal proteostasis. Preliminary data suggest that the loss of miR-211 disrupts lysosomal degradation and increases amyloid accumulation in neurons. Our aim is to elucidate the mechanisms by which miR-211 controls autophagy and lysosomal function via the Ezrin/AKT/mTOR signalling axis. Through an interdisciplinary approach integrating molecular biology, omics technologies and preclinical models we aim to develop innovative therapeutic strategies for Alzheimer’s disease by targeting the miR-211 pathway.
Neurodevelopmental disorders: study of pathogenic mechanisms and identification of new potential therapeutic targets
2024-2027 | FONDAZIONE CRT
Sara Bonzano (PI)
Mitochondrial dysfunction is emerging as a common feature in pediatric neurodevelopmental disorders (NDDs), with clinical presentations ranging from autism to intellectual disability, visual deficits, and neurodevelopmental delay, for which there are currently no cures. Recently, we have identified impaired mitochondrial function in nervous tissue in murine models of a rare neurodevelopmental disorder (BBSOAS) caused by mutations in the gene encoding the transcription factor Nr2f1. Our data also reveal that Nr2f1 regulates a network of genes involved in mitochondrial function in neurons, indicating that mitochondrial dysfunction plays a key role in the pathogenesis of BBSOAS. The project aims to test this hypothesis by elucidating the link between Nr2f1-mitochondria-neuronal dysfunction and the involved cellular/molecular mechanisms. The anticipated results will contribute to understanding the causative factors of BBSOAS and, more broadly, numerous neurodevelopmental disorders, opening new therapeutic perspectives.
Discovering the Effectors of LIfestyle-driven Memory enhancement via InflammaTion – DELIMIT
2023-2026 | Bando PRIN-PNRR 2022 Ministero dell’Università e della Ricerca
Serena Bovetti (PI NICO)
PI PARTNER
Marco Mainardi, Università degli Studi di Padova, Department of Biomedical Sciences, Padova (Italy)
Mathew Diamond, Scuola Internazionale Superiore di Studi Avanzati/International School for Advanced Studies (SISSA), Trieste
A healthy lifestyle—encompassing physical activity, cognitive stimulation, and social engagement—represents an effective strategy for reducing the risk of neurological disorders and enhancing cognitive performance. However, the impact of lifestyle interventions varies considerably among individuals due to physiological and clinical heterogeneity. Using environmental enrichment (EE) in mice as an experimental model, the proinflammatory chemokine CCL11 has been identified as a key molecular mediator linking lifestyle factors to cognitive outcomes. The objective of this project is to further elucidate the role of CCL11 in these processes by investigating its interactions with microglia and oligodendrocytes, two types of glial cells that play essential roles in central nervous system plasticity.
Characterization and modulation of “immature” neurons: a potentially exploitable reservoir of non-newly generated cells involved in plasticity of the rodent and human cerebral cortex2023-2026 | Bando PRIN-2022 – Ministero dell’Università e della Ricerca
2021-2025 | Bando “TRAPEZIO” – Fondazione Compagnia di San Paolo
Luca Bonfanti (PI)
Neural plasticity is ensured by the rewiring of neural connections and, to a lesser extent, by the addition of new neurons produced by stem cells (adult neurogenesis).
Recently, a great interest was aroused by the discovery of a new population of adult cortical “immature neurons” (cINs) that are born pre-natally, then continuing to express markers of immaturity shared with adult newlyborn neurons. These cINs ideally represent a new form of delayed neurogenesis (“without division”) involving neural elements “frozen” in a standby, undifferentiated mode before birth.
They might represent a potential reservoir of young cells with a still unidentified role in an adult brain region lacking neural stem cells: the cerebral cortex. The cINs were thought to be restricted to the piriform cortex of rodents, yet an unexpected twist occurred recently, when Unit 1 of this project showed high phylogenetic variation in mammals, with abundant occurrence in the neocortex of large-brained, gyrencephalic species (La Rosa et al., eLife 2020).
This finding opens the exciting avenue for a form of structural plasticity mimicking adult neurogenesis in the cortical mantle, nevertheless very little is known about the physiological function/modulation/mobilization of these cells. Data obtained using DCX-Cre-ERT2/Flox-EGFP transgenic animals, a reporter mouse line for cINs, confirmed that cINs do not die with age. On the contrary, most of them mature as cells with more complex dendritic arborisation and integrate into the piriform cortex network. On these bases, it is of paramount importance to understand if these neurons can represent an additional source of cortical young, undifferentiated cells in humans for a brain region of utmost importance in higher brain functions, not endowed with stem cell-driven neurogenesis.
This project is intended to answer fundamental unexploited questions, such as: i) the possible modulation of cINs by different environmental/experimental conditions; ii) their role in brain plasticity; iii) their occurrence, development, distribution, amount in humans.
We will address such issues through collaboration of three highly complementary Units
– Turin, analysis of immature neurons in humans;
– Milan, molecular characterisation of cINs and assessment of their functional integration in the neuronal network;
– Rome, modulation of cINs in different experimental conditions), which will organize their work in three well-integrated, interconnected Work Packages.
cIN development and modulation will be studied in the piriform cortex of mice models allowing their specific identification, and in human fetal and adult brains.
Imprinted SCENTs: odour control of mate preference
2021-2025 | Bando “TRAPEZIO – Paving the way to research excellence and talent attraction” – Fondazione Compagnia di San Paolo
Serena Bovetti (PI)
The ability to establish sensory-related memories during infancy is a shared process among several animal species, including humans. Encoding and recalling past cues is fundamental in a wide spectrum of essential animal behaviours. One among many is sexual imprinting, a process of instinctive learning that happens early during development and guides adult mate selection. More specifically, during early postnatal development individuals acquire memories of the odours, vocalizations, and other characteristics of their parents (or siblings), and then utilize this information to select their mates as adults. This indicates that different sensory cues, including odours, are stored during animal development and later recalled driving behavioural choices of adult subjects. While imprinting behaviour has been extensively studied in different animal species, little is known about the sensory processing underlying representation of imprinted cues and how they shape brain circuits for mate selection. In the proposed project, we will focus on the role of olfaction in sexual imprinting to investigate when and how early-life exposure to relevant odours shapes their representation in adults.
Past
Sounds and pheromones: neural networks merging olfactory and acoustic cues in sexual imprinting
November 2020 – October 2023 | Human Frontier Science Program Research Grant
Serena Bovetti, Paolo Peretto; NICO, Università di Torino, Italy
Sylvain Gigan, Claudio Moretti; Laboratoire Kastler-Brossel, Sorbonne Université Ecole Normale Supérieure, Paris, France
Dustin Penn, Sarah Zala; Konrad Lorenz Institute of Ethology, Veterinary Medicine University, Vienna, Austria
Our main aim in this project is to identify the regions of the brain and the specific neural circuits that are influenced by sexual imprinting during postnatal development, and determine how these circuits influence adult mating behavior in wild house mice. To achieve these aims, we created a new interdisciplinary collaboration between three groups with very different expertise; indeed the project integrates neuroscience, ethology and advanced optics.
