Understanding causal mechanisms in biological systems is essential for decoding complex physiological and pathological processes. Causal learning, a branch of machine learning, establishes quantitative relationships between molecular variables, revealing regulatory dynamics. Identifying interactions between master regulators, their target transcripts, and external interventions is crucial for...
Medulloblastoma (MB) is the most common pediatric brain tumor, and current therapies fail in about 30% of cases due to fatal recurrences. To address effective therapeutic strategies against MB, a better modeling of the tumor microenvironment is needed.
Here, we firstly developed an orthotopic xenotransplantation model of human MB in wild-type mouse embryos, which recapitulates the MB...
"Neurodevelopmental Disorders (NDDs) include a wide range of conditions characterised by impairments affecting the development of the central nervous system, with implications for cognitive, motor, behavioral, and social functioning.
To tackle the complexity of the mechanisms underlying these dysfunctions suitable experimental models are needed. While animal models and 2D in vitro cultures...
Understanding astrocyte heterogeneity is crucial for gaining insights into the development and function of the central nervous system. While the main types of cerebellar astrocytes can be identified based on their morphology and location, it remains unclear whether this classification reflects the full extent of cerebellar astrocyte heterogeneity. Furthermore, our overall
knowledge on their...
"Huntington disease (HD) is a late-onset and progressive neurodegenerative condition caused by an expanded CAG repeat residing in exon1 of the Huntington gene (HTT). In recent years, there has been a shift in prospective about the pathogenic mechanisms underlying HD, moving beyond traditional protein-centric vision to embrace new DNA-based driving hypothesis. Accordingly, inherited CAG repeats...
When neurons are stimulated, a cascade of intracellular signaling events alters the chromatin landscape, leading to changes in gene expression. This process is essential for activity-dependent plasticity, learning, and memory. Activity-regulated genes often engage in chromatin looping, bringing enhancers and promoters into proximity.
However, the precise mechanisms governing 3D epigenome...
Neurological disorders are highly prevalent (3 billion people around the globe are suffering from it), and due to the challenges associated with studying these pathologies in humans, the importance of in vitro human models is growing. The use of in vitro human models provides a more accurate representation of human biology, thereby enhancing our understanding of neurological disorders and the...
Ataxia-telangiectasia (A-T) is a rare, autosomal recessive disorder affecting multiple systems, characterized by progressive cerebellar atrophy, neurodegeneration, and cognitive decline. A key neuropathological feature is the loss of Purkinje and granule cells in the cerebellum. Mutations in the ATM gene, located on chromosome 11q22-23, underlie A-T. This gene encodes ATM, a serine/threonine...
B7-H3, also known as CD276, is an immune checkpoint molecule and has emerged as a significant player in cancer tumorigenesis across multiple malignancies, including the pediatric brain tumors medulloblastoma, gliomas and ependymoma. Its exact role in tumor formation, however, is unclear. Our investigations demonstrated high expression levels of B7-H3 in brain tumors, irrespective of tumor type...
Chiari Malformation Type I (CM1), characterized by cerebellar tonsillar herniation exceeding 5 mm through the foramen magnum, represents the most common subtype of Chiari Malformations, a group of developmental disorders involving posterior fossa deformities. Despite its prevalence characterized by a strong female predominance, its described neuroanatomical features, neurological symptoms, and...
Brain organoids can provide major insights into neurodevelopment and its disruption in neuropsychiatric disorders. To capture how individual chromatin remodellers and their dosage shape developmental trajectories, we profiled by single-cell RNA-seq brain organoids derived from a group of paradigmatic neurodevelopmental disorders (NDDs) caused by mutations in chromatin regulators. Currently...
Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet current therapies have limited efficacy. Immune responses, primarily from microglia and regulatory adaptive immune cells, are closely linked to the pathological changes in amyloid-beta and tau observed in AD. We previously demonstrated that microglia in adult mice can be replaced through bone marrow transplantation...
Fragile X Syndrome (FXS) is a rare neurodevelopmental disorder, representing a leading cause of inherited intellectual disability and monogenic cause of autism spectrum disorders. It results from abnormal CGG repeat expansion in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, leading to its silencing and loss of FMRP, an RNA-binding protein crucial for synaptic plasticity and...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF).
We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells...
Cortical development is relatively slower in humans compared to other species. Here, we investigated whether our neurodevelopmental tempo also differs from that of our closest extinct relatives, the Neanderthals and Denisovans. To tackle this, we selected, through comparative paleogenomics analyses and machine learning, a sapiens-specific single nucleotide variant virtually fixed in...
Rett syndrome is a neurodevelopmental disorder in which the involvement of astrocytes is recognized. Previous work from our laboratory underlined how synaptotoxic factors, such as IL-6, aberrantly expressed by MEPC2 knock-out astrocytes lead to detrimental effects on the synapses in development. Moreover, astrocyte role during development is to provide synaptotrophic factors which could be...
FOXP1 is a transcription factor critical for human brain function from early development. Indeed, heterozygous mutations in this gene cause FOXP1 syndrome, a rare neurodevelopmental disorder characterized by language impairment, intellectual disabilities, and autistic traits [1]. FOXP1 levels are affected also in Huntington disease and cancer. However, mouse models of FOXP1 haploinsufficiency...
"In the last decade, the widespread adoption of hiPSC technologies and their differentiation into brain organoids (BOs), together with the massive use of single-cell (SC) transcriptional profiling, has provided a significant boost to the study of human brain pathophysiology. This progress has enabled time-resolved characterization of cellular players and their interactions, which is...
Mutations in the SOX2 gene lead to defects in the development of multiple brain regions, causing blindness, intellectual disabilities, and seizures. SOX2 is a transcription factor that regulates many genes, some of which, when mutated, are involved in other neurodevelopmental disorders (NDDs).
Using RNA sequencing, we identified over a thousand genes that are downregulated following Sox2...
Pooled CRISPR screenings are powerful functional genomics tools to assess how perturbing gene expression alters cellular fitness, differentiation, and transcriptomic landscapes in complex biological models. When studying systems that recapitulate brain development, it is crucial to resolve changes in developmental trajectories and cellular dynamics at single-cell resolution, as diverse neural...
Cohen syndrome (CS) is a rare autosomal recessive disorder caused by a biallelic mutation in the VPS13B gene. It is a heterogeneous genetic disorder characterized by microcephaly, hypotonia, intellectual disability, neutropenia, and retinal degeneration. VPS13b is localized at the Golgi apparatus and is essential for the maintenance of organelle architecture. To understand how VPS13b mutation...
Myelination is essential for neuronal conductivity and brain function, yet the molecular mechanisms regulating this process remain unclear, limiting therapeutic advancements for demyelinating disorders. Our study aims to investigate the role of the WW domain-containing oxidoreductase (WWOX) gene in CNS myelination. We previously showed that murine Wwox deletion leads to hypomyelination and...
Glioblastoma (GBM) is an aggressive and highly heterogeneous brain tumor, making treatment development particularly challenging. A key contributor to GBM's heterogeneity is glioblastoma stem cells (GSCs), which possess critical properties such as self-renewal, plasticity, and resistance to therapy. These characteristics are pivotal in tumor progression and recurrence, highlighting the need for...
PRR12 (Proline rich 12) gene is encoding for a nuclear protein but its function in chromatin regulation remains elusive. We collected preliminary evidence that PRR12 can interact with the transcription factor SOX2, a pivotal regulator of neural stem cell identity and self-renewal. In humans, heterozygous loss-of-function mutations cause the Neurocular syndrome. The aim of our project is to...
The mammalian cerebral cortex arises from neocortical and hippocampal primordia (Ncp and Hcp respectively), which initially display cellular composition similarities and several molecular markers. Their trajectories diverge significantly during development, resulting in functionally distinct structures. The molecular mechanisms orchestrating the progressive regionalization of the Ncp and Hcp...
SYNGAP1, encoding Ras/Rap GTPase-activating protein, is a critical gene involved in synaptic signaling and neurodevelopment. Mutations in SYNGAP1 are associated with intellectual disability and autism spectrum disorder (ASD). However, the specific functions of its multiple isoforms, generated by alternative splicing and transcription start sites, remain poorly understood. Current methods for...
Progressive Myoclonus Epilepsy Type I (EPM1) is a rare form of epilepsy, caused primarily by mutations in the CSTB gene.
Our previous studies using cerebral organoids derived from somatic cells of EPM1 patients (EPM1-CO), have shown that CSTB is implicated in human cortical development and plays a role in extracellular signaling, cell proliferation, interneuron recruitment and synapse...
Background:
Consanguineous unions enhance the risk of homozygous loss-of-function (LoF) variants in the subsequent generations. Hence, highly endogamous populations like Pakistan provides an opportunity to identify naturally occurring human knockouts (hKOs) to further understand the complexity of human genome. We designed this study to identify novel recessive candidate genes underlying...
Human somatic neural stem cells (NSCs) are emerging as promising advanced therapy medicinal products for treating neurodegenerative and demyelinating disorders. However, challenges remain, including the large-scale production of donor cells under GMP conditions and the necessity of immunosuppressive regimens in allogeneic transplant settings. Human induced pluripotent stem cell-derived neural...
Globoid Cell Leukodystrophy (GLD) is a lysosomal storage disorder due to mutations in the galactosylceramidase (GALC) gene, which is essential for sphingolipid metabolism. GALC deficiency leads to the accumulation of toxic psychosine, causing demyelination, neurodegeneration, and neuroinflammation in the central and peripheral nervous systems. While dysfunctional oligodendrocytes (OLs) were...
"Initial evidence for adult neurogenesis in the mammalian brain was already obtained in the 60s of the last century, when newly generated neurons were first described in the rat brain (Altman, 1962). Since then, numerous studies have provided experimental evidence of adult neurogenesis in several mammalian species, from rodents to non-human primates and humans. Despite the extensive...
Whether and how the impact of environmental exposures can be inherited, with parental environments shaping phenotypes across generations independent of DNA sequence carried in gametes, is a fundamental question in biology, with far-reaching implications for human health. Despite evidence of such epigenetic inheritance in animals, the mechanisms and relevance to humans remain elusive due to...
Autism spectrum disorder (ASD) is highly inherited and arises from a complex interplay between three major categories of genetic risk: common polygenic variation, rare inherited and de novo mutations. The efforts to identify rare variants of large effect have mainly focused on the common variants in coding regions of the genome. However, rare genetic variants, especially in non-coding regions,...
Studying the epigenetic landscape during the transition between pluripotency and the germline at multi-omics level enables to study the molecular basis of germ cell tumorigenesis and epigenetic inheritance. We recently developed and characterised a protocol to differentiate human pluripotent stem cells (hPSC) into Primordial Germ Cell-Like Cells (hPGCLC), and to go back again to pluripotency,...
"Duchenne muscular dystrophy (DMD) is an X-linked progressive neuromuscular disorder caused by mutations in the DMD gene, resulting in the absence of dystrophin protein. In healthy muscle, only the full-length dystrophin isoform Dp427m is expressed, while the brain expresses the full-length isoforms Dp427c and Dp427p, and the shorter isoforms Dp140 and Dp71/40. Depending on the position of the...
"During neocortex development neural stem progenitor cells display polarity features that are fundamental in determining their identity and fate. Interestingly, Golgi apparatus (GA) is differentially positioned in the two main neural stem cell types, apical and basal progenitors (APs and BPs, respectively). GA is known to be the main hub for glycosylation and defects in GA and glycosylation...
Background/Objectives. ADLD is a rare neurodegenerative disorder caused by LMNB1 overexpression due to gene duplications (classical ADLD) or noncoding deletions in the locus (atypical ADLD). Our group collected > 20 families worldwide carrying structural variants (SVs) in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1...
"CAPRIN1 is a ubiquitous protein involved in cell proliferation and migration. In neurons, it regulates the transport and translation of mRNAs involved in synaptic plasticity. We have previously associated CAPRIN1 loss-of-function variants with a rare autosomal dominant neurodevelopmental disorder (NEDLAAD, OMIM #620782), showing several defects on hiPSCs-derived neurons, including decreased...
The polygenic underpinnings of human neurodiversity require new maps to trace its neurodevelopmental physiopathology. Brain organoids can provide major insights into neuropsychiatric disorders, yet the focus is still on one or a few specific disorders at a time, typically caused by highly penetrant genetic mutations studied in isolation. CRISPR-based screenings of heterogenous collections of...
Microphthalmia, Anophthalmia, and Coloboma (MAC) are severe ocular malformations resulting
from mutations in both protein-coding genes, such as the transcription factor SOX2, and non-coding
regulatory elements. Approximately 50% of affected individuals lack a definitive molecular diagnosis based
on exome sequencing aimed at detecting protein-coding genes mutations, suggesting that...
Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Microglia, the immune surveillant of the brain, express Triggering Receptor Expressed on Myeloid Cell 2 (TREM2), which regulates synapse elimination and neuronal cell metabolism during development. Using a maternal immune activation model with...
The Epstein-Barr Virus (EBV) is a DNA virus belonging to the Herpesvirus family. EBV infections are extremely common, and linked to various diseases. Recent studies have highlighted the role of herpesviruses in the central nervous system (CNS) and some reports suggest a possible link between EBV infection and Rasmussen’s encephalitis. This is a progressive neurological disease that primarily...
Microglia are the principal resident immune cells of the central nervous system (CNS) representing 5-12% of the total cell population in the brain. They are of myeloid origin and their survival and maintenance depend on several cytokines. Microglia play a role in development of the CNS and are constantly engaged in detecting changes in their environment, maintaining homeostasis and protecting...
Comparative socio-genomics is an emerging field that integrates behavioral science, molecular, and evolutionary biology, genomics, neuroscience, and bioinformatics to explore the genetic basis of social behavior across species.
Our aim is to uncover the genetic roots of social behavior to infer novel risk genes for autism, a neurodevelopmental disorder characterized by social and...
Induced pluripotent stem cell (iPSC) models combined with single-cell transcriptomics enable the study of cellular consequences resulting from human disease alleles, particularly in early-onset developmental disorders. A significant bottleneck lies in the scalability of iPSC-based experiments. Pooled cell culture or ‘cell villages’ has emerged as a key strategy to enable large-scale studies....
Peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) and dominant optic atrophy (ADOA), are frequently associated with mitochondrial dysfunction. Through transcriptomic analysis, we identified the mTOR/AKT axis as a key regulator of mitochondrial homeostasis and quality control. We investigated fibroblast lines derived from three patients: two carrying mutations in mitochondrial...
Mental health outcomes are shaped by a complex interplay between genetics and environmental factors throughout life. Early-life exposure to endocrine-disrupting chemicals (EDCs), widespread environmental compounds that interfere with the endocrine system, has been associated with neurodevelopmental disorders (NDDs). Our research aims to identify risk and protective factors for mental health by...
Primary cilia (PCs) are single-copy organelles functioning as important signaling hubs for multimodal stimuli. Dysregulation of PCs leads to syndromic phenotypes (including hindbrain malformations) and developmental disorders referred to as primary ciliopathies. Aberrant activation of ciliary pathways is a major driver in the formation of brainstem and cerebellar tumors. It is well known that...
The human brain is a complex organ, and its features of neurodevelopment and disease remain largely unexplored due to limited accessibility of living tissue. Recently, the human induced pluripotent stem cells (hiPSC) technology allowed to model the human brain in vitro, generating 3D organoids.
We developed brain and region-specific brainstem organoids, characterized them by fluorescent IHC...
Neurons are capable of adapting their gene expression in response to electrical signals, converting synaptic activity into dynamic and lasting functional changes. This activity-dependent transcription is tightly regulated by neuronal firing and specialized pathways, shaping neural circuits and synaptic plasticity (Greenberg et al., 2018). Sustained hyperexcitability can lead to several...
"Autosomal Dominant Leukodystrophy (ADLD) is a rare genetic disease associated with white matter loss in the CNS and characterized by autonomic dysfunction and motor impairment. The genetic cause is the presence of three copies of the lamin B1 (LMNB1) gene, which encodes for a structural protein located in the nuclear lamina. Pathogenic mechanisms in ADLD have only initially been explored and...
Long COVID refers to persistent symptoms lasting over a year after a SARS-CoV-2 infection, with no other underlying cause. These include neurological symptoms (NeuroCOVID) such as memory disorders and concentration impairment, which disrupt daily life and can persist even after other viral symptoms resolve. The NeuroCOV Consortium was established to address the emerging clinical need to...
PD is characterized by the degeneration of dopaminergic neurons of the Substantia Nigra pars compacta (SNpc), disruption of dopamine (DA) homeostasis, and the formation of Lewy bodies (LB), intracellular protein inclusions primarily composed of α-synuclein (α-syn). Alpha-syn plays a key role in synaptic function regulating vesicle trafficking, membrane dynamics, and neurotransmitter release....
Medulloblastomas are malignant cerebellar tumors that represent approximately 20% of all pediatric brain tumors. Molecular profiling categorizes these tumors into four subgroups: WNT, SHH, Group 3 (G3), and Group 4 (G4). G3 and G4 tumors account for more than 65% of pediatric cases and exhibit the highest rates of metastasis, relapse, and mortality. Current models predominantly reflect G3...
In the mature cerebellum astrocytes with different morphologies occupy distinct cerebellar territories. This enables their classification into 4 distinct types based on their morphology and topographical localization. Such a well-defined classification offers an excellent platform to challenge the concept of astrocyte heterogeneity as well as to attempt cross-correlating the multilevel...
βII-spectrin, encoded by SPTBN1, binds F-actin to form a submembrane cytoskeletal lattice that organizes transmembrane proteins in neurons. We discovered that heterozygous SPTBN1 variants cause a neurodevelopmental disorder marked by developmental delay, intellectual disability, ASD, ADHD, epilepsy, and cortical deficits –SPTBN1 syndrome. Brain βII-spectrin haploinsuficient mice display...
Glioblastoma (GBM) is an aggressive malignant tumor arising from neuroglial progenitor cells, characterized by its remarkable ability to infiltrate healthy brain parenchyma. Multiomic studies have revealed a complex heterogeneity, identifying three distinct GBM subtypes: proneural, mesenchymal, and classical. In this study, we focused exclusively on the proneural subtype, using multiomics...
Genomic studies have identified an ever-expanding set of de novo gene mutations in Epilepsy Risk Genes (ERGs) conferring high risk for neurodevelopmental epilepsy. ERGs are known to converge on synaptic and ion channel pathways in neurons, but we currently lack a systematic annotation of their functional genomic features.
To address this, we collated twelve diverse multiomic data sets...
Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722) is a rare neurodevelopmental disorder caused by mutations in NR2F1, a transcriptional regulator essential for brain and visual system development. Patients display a broad clinical spectrum—including intellectual disability, optic atrophy, autistic traits, and hypotonia—reflecting NR2F1 pleiotropic roles and suggesting...
Neural organoids provide a great tool to decipher human brain diseases at the molecular and physiological levels. The organoids are of great value in understanding neurodevelopmental diseases, as they can reflect changes occurring even in the prenatal period. Those diseases are often accompanied by aberrant changes in the formation of dendritic spines harboring excitatory synapses. Yet, none...
"Three-dimensional neural models derived from human-induced pluripotent stem cells (hiPSCs), such as organoids and assembloids, are essential tools for replicating key features of human brain development. They play a vital role in advancing research on neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Real-time, label-free measurement of electrical activity is needed...
The FOXG1 transcription factor is a crucial regulator of embryonic brain development. Pathogenic FOXG1 variants cause FOXG1 syndrome. Although structural variants (SVs) in the non-coding region downstream of FOXG1 have been reported in 38 individuals with similar characteristics, the regulatory pathomechanisms remain unknown.
We identified a de novo non-coding deletion in an individual with...
The advent of three-dimensional (3D) biological models, particularly organoids, has revolutionized biomedical research by providing physiologically relevant in vitro models that mimic the complexity of human tissue and organs, samples that may not be routinely available to study. Amongst the fields more impacted by this revolution is neuroscience, thanks to the development of several protocols...
"Huntington’s disease (HD) is a devastating neurodegenerative disorder characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum, leading to severe motor, cognitive, and psychiatric impairments. As no disease-modifying treatments are currently available, cell replacement therapy has emerged as a potential promising approach to restore striatal function.
From this...
Epileptic disorders represent high burden diseases characterized by recurrent and unprovoked seizures, which are due to the excessive and hypersynchronous discharge of neuronal networks. Strikingly, 75% of epilepsies arise during childhood, such as developmental epileptic encephalopathies (DEEs), which are genetic conditions characterized by recurrent and drug-resistant seizures and by...
"SYNGAP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous de novo mutations in the SYNGAP1 gene. Affected individuals present with a complex clinical phenotype, including intellectual disability, developmental epileptic encephalopathy, autism spectrum disorder, and other comorbidities. SYNGAP1 encodes SynGAP, a Ras GTPase-activating protein critical for excitatory synapse...
The bidirectional communication between placenta and embryonic brain during pregnancy, known as placenta-brain axis, is an important aspect of embryonic development in placental mammals, including humans. Recently we have shown that the maternal environment of pregnancy dominantly regulates the length of neurogenesis in the embryonic brain. The brain vascular system is a key intermediate to...
"Weaver syndrome (WVS) is a multisystem disorder, characterized by pre- and post-natal overgrowth and intellectual disability. WVS genetic cause was identified in heterozygous mutations in Polycomb repressive complex 2 (PRC2). This complex catalyzes the tri-methylation of Lysine 27 on histone 3 (H3K27me3), promoting transcriptional repression during corticogenesis. Our knowledge about the...
Among the myriad captivating relationships forged by the gut microbiota (GM) within the human body, one of the most intriguing and intricate is the connection between the gut and the brain. This pathway has garnered increasing interest in recent years as a potential mechanism involved in the complex interplay of processes related to neurodevelopment, especially in critical periods as the...
"The development of the human cortex entails a complex series of cell fate decisions that are both genetically encoded and epigenetically orchestrated. Understanding how these mechanisms work at the single-cell level is crucial for deciphering the molecular basis of neuronal development and disease. In this context, we investigate the role of chromatin modulators in controlling neural cell...
During brain development, Polycomb group proteins regulate the spatiotemporal expression of neurodevelopmental genes to control cell fate decisions. Polycomb repressive complex 1 (PRC1) is a key regulator of neural development and is frequently deregulated in neurodevelopmental disorders. PRC1 mediates gene repression through both its catalytic activity (H2AK119ub deposition) and non-catalytic...
Comparative genomic studies between contemporary and extinct hominins revealed key evolutionary modifications, but their number has hampered a system level investigation of their combined roles in scaffolding modern traits. Through multi-layered integration we selected 15 genes carrying nearly fixed sapiens-specific protein-coding mutations and developed a scalable design of combinatorial...
RNA ligases play critical roles in RNA repair, splicing, and editing, but their significance in vertebrate neural development remains poorly understood. Here, we investigated RNA ligase 1 (Rlig1), a recently characterized 5’-3’ RNA ligase, using zebrafish (Danio rerio) as an in vivo model. We discovered that rlig1 mRNA is maternally deposited and later becomes enriched in the developing brain...
Thyroid hormone receptor alpha (THRα) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. In mammals, THRα has two major splicing isoforms, THRα1 and THRα2. The better-characterized isoform, THRα1, is a transcriptional stimulator of genes involved in cell metabolism and growth. The...
Parkinson’s Disease (PD) is a neurodegenerative pathology characterized by loss of dopaminergic neurons (DANs) of the substantia nigra, accumulation and aggregation of 𝜶-synuclein (αSYN), and neuroinflammation. Neuroinflammation is a risk factor to PD development, moreover the pathology is characterized by a correlation between levels of proinflammatory cytokines and disease severity, a...
Congenital Central Hypoventilation Syndrome (CCHS) is a rare life-long threatening genetic disorder caused by mutations in the PHOX2B gene, a master transcription factor of the autonomic nervous system (ANS). It is characterized by ANS dysfunctions, most importantly a deficient control of autonomic ventilation that leads to hypoventilation during sleep. In vivo and in vitro studies suggest...
Klinefelter syndrome (KS, 47,XXY) is the most prevalent aneuploidy in males (1:400-1:600). High-grade sex chromosome aneuploidies (HGA-SCAs), such as 48,XXXY, and 49,XXXXY are rarer conditions occurring in 1:40.000-1:80.000 males. KS and HGA-SCA patients exhibit a broad spectrum of neuronal impairment, including cognitive deficits, seizures, autistic traits, and motor, speech, and language...
The polygenic architecture of human neurodiversity requires new maps to model the developmental continuum it underpins. While pluripotent stem cell and brain organoid modelling has begun to provide major insights into the pathogenesis of neuropsychiatric disorders, the focus is still on one or, at best, a few specific disorders at a time, mostly caused by highly penetrant genetic mutations and...
Lipid droplets (LDs) are intracellular lipid storage organelles. Recently, we showed that adult mouse neural stem/progenitor cells (NSPCs) contain a large number of LDs, which directly influence NSPC proliferation and metabolism. To further study LDs in the brain, we have developed a novel endogenous fluorescent LD reporter mouse (tdTom-Plin2 mouse) to allow staining-free visualization of LDs....
During neural development, neuronal stem cells differentiate into functional neurons that make up the human brain. Transcription regulators ensure the timely expression of genes required for neuronal differentiation. Perturbed transcription can cause neurological and neurodevelopmental disorders as well as lead to the development of cancer. It is therefore crucial to identify and characterize...
Neurons mediate the reception and transmission of nervous stimuli with their polarized shape and processes. Each nervous cell makes thousands of synaptic contacts with other cells. Synapses are well characterized in their protein content but there is less concordance about the resident RNA species that contribute to synapse function and maintenance. mRNAs that localize at synaptic boutons can...
The recent expansion of multi-omic molecular methods, including transcriptomics, proteomics, epigenomics and whole-genome sequencing, has led to huge improvements in the diagnosis and research of rare diseases, such as neurodevelopmental disorders (NDDs). The accuracy of these methods in pathology profiling is in part determined by the closeness of the tested biological sample to the diseased...
TMEM151A, an almost unknown gene, has been recently associated to Paroxysmal Kinesigenic Dyskinesia (PKD), an autosomal dominant movement disorder. Our project aims to identify the role of TMEM151A in the brain from both a physiological and pathological point of view through a multi-level approach. We studied the topology of TMEM151A and showed that it is a membrane protein with two...
Spatial multi-omic technology has the potential to reveal the molecular foundations of neurodegeneration, uncovering both shared pathological responses and discrete signatures of vulnerability across clinically distinct neurodegenerative diseases. Using GeoMx spatial profiling, we quantified mRNA in CA1 pyramidal neurons with and without tau pathology in 6 primary age-related tauopathy (PART...
SUMOylation pathway is a post-translational modification process that regulates the function of hundreds of proteins by SUMO protein attachment. This three-step pathway requires activation of SUMO proteins by the E1 enzyme, transfer to the E2 conjugating enzyme and SUMO-protein ligation directly or through E3 ligase. Defects in SUMOylation are being linked to abnormal neuronal development and...
This study presents a comprehensive computational and experimental analysis of long non-coding RNAs (lncRNAs) in cortical neuron differentiation from human embryonic stem cells (hESCs). Using a systematic workflow, we identified lncRNAs overexpressed at late stages of neural differentiation and characterized their expression, subcellular localization, sequence features, and regulatory...
With the identification of ~150 modifications found in RNA, epitranscriptomic modifications emerged as critical posttranscriptional modulators of brain development and function. tRNAs, the adaptor molecules that deliver specific amino acids to the polypeptide chain during translation, are the most modified RNA species, with an average of 13 modifications per tRNA. These modifications,...
In mammals, neural stem cells proliferation and differentiation contribute to organize sophisticated brain architecture during neocortical development.
Among different classes of progenitors, apical progenitors (APs) possess unique apicobasal polarity that has driven increasing interest in understanding how subcellular regulation of gene expression occurs within these cells. Similarly to...
The choroid plexus (ChP), a vascularized structure, plays a pivotal role in cerebrospinal fluid (CSF) production and brain homeostasis by regulating ion transport, nutrient delivery, and waste clearance. Beyond these functions, the ChP acts as a sensor and modulator of environmental signals, influencing brain development and contributing to the pathophysiology of neurodevelopmental disorders....
Neurodevelopmental disorders (NDDs) encompass a heterogeneous spectrum of conditions that impact the development of the nervous system, leading to impairments in cognitive function, behaviour, and social abilities. The genetic basis of these disorders ranges from highly penetrant monogenic diseases to complex polygenic influences, in addition to a wide array of environmental factors. Despite...
DLG4-related Synaptopathy, also known as SHINE syndrome, is a newly identified neurological disorder associated with variants in the Discs Large Homolog 4 (DLG4) gene, encoding for the post-synaptic density 95 (PSD-95) protein, the most abundant scaffolding MAGUK protein in excitatory post synaptic densities (PSDs). Owing to the diversity of signalling pathways associated with PSD-95, 225 DLG4...
Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of Arylsulfatase A (ARSA), a critical enzyme that breaks down sulfatides. Accumulation of sulfatides results in neurological manifestations related to white matter loss in the central and peripheral nervous systems (CNS, PNS), accompanied by neuroinflammation and neurodegeneration.
Ex...
Parkinson’s disease (PD) is a pervasive neurodegenerative disorder characterized by a loss of dopaminergic neurons starting from the substantia nigra, which triggers motor and cognitive symptoms. Existing treatments such as dopamine replacement therapies and deep brain stimulation (DBS) provide symptomatic relief, but they are limited by side effects and transient efficacy. Cell replacement...
Cell differentiation towards neurons undergoes global changes in three-dimensional (3D) genome organization and gene expression. Our integration of multi-omic data generated in the frame of the Functional ANnoTation Of the Mammalian genome (FANTOM6) to chart interplay of between RNA-DNA and DNA-DNA interactions in the nucleus during in vitro differentiation of human induced pluripotent stem...
