migration

Cellular Crosstalk in Brain Development, Evolution and Disease

Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.

Cellular and genetic mechanisms of cerebral cortex folding

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.

Cellular crosstalk in Neurodevelopmental Disorders

Cellular crosstalk is an essential process during brain development and it is influenced by numerous factors, including the morphology of the cells, their adhesion molecules, the local extracellular matrix and the secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the correct development of the human brain. Hence, we combine the in vivo mouse model and the in vitro human-derived neurons, cerebral organoids, and dorso-ventral assembloids in order to better comprehend the molecular and cellular mechanisms involved in ventral progenitors’ proliferation and fate as well as migration and maturation of inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders. We particularly focus on mutations in genes influencing cell-cell contacts, extracellular matrix, and secretion of vesicles and therefore study intrinsic and extrinsic mechanisms contributing to the formation of the brain. Our data reveal an important contribution of cell non-autonomous mechanisms in the development of neurodevelopmental disorders.

Regulation of Cerebral Cortex Morphogenesis by Migrating Cells

How Migration Policy Shapes the Subjective Well-Being of the Non-immigrant Population in European Countries

Existing studies show that there is a positive association between pro-migrant integration policies and the subjective well-being of immigrants. However, there is a lack of research elucidating the relations between migrant integration policies and the subjective well-being of the host (i.e., non-migrant) population. This study is based on European data and uses multilevel analysis to clarify the relations between migrant integration policy (both as a whole and its 8 separate components such as: Labour market mobility and Family reunion) and the subjective well-being of the non-immigrant population in European countries. We examined relations between the Migrant Integration Policy Index (MIPEX) for 22 countries in Europe and subjective well-being, as assessed by the European Social Survey (ESS) data. The results demonstrated that there is a positive relation between the MIPEX and subjective well-being for non-immigrants. Considering different components of the MIPEX separately, we found most of them being positively related to the subjective well-being of non-immigrants. As no negative relationship was identified between any of the eight MIPEX components and subjective well-being, policies in favour of immigrant integration also seem to benefit the non-immigrant population.

Modulation of oligodendrocyte development and myelination by voltage-gated Ca++ channels

The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently established that the activity of voltage-gated Ca++ channels is crucial for the adequate migration, proliferation and maturation of oligodendrocyte progenitor cells (OPCs). Furthermore, we have found that voltage-gated Ca++ channels that function in synaptic communication between neurons also mediate synaptic signaling between neurons and OPCs. Thus, we hypothesize that voltage-gated Ca++ channels are central components of OPC-neuronal synapses and are the principal ion channels mediating activity-dependent myelination.

Investigating the sun compass in monarch butterflies (Danaus plexippus)

Every autumn, monarch butterflies migrate from North America to their overwintering sites in Central Mexico. To maintain their southward direction, these butterflies rely on celestial cues as orientation references. The position of the sun combined with additional skylight cues are integrated in the central complex, a region in the butterfly’s brain that acts as an internal compass. However, the central complex does not solely guide the butterflies on their migration but also helps monarchs in their non-migratory form manoeuvre on foraging trips through their habitat. By comparing the activity of input neurons of the central complex between migratory and non-migratory butterflies, we investigated how a different lifestyle affects the coding of orientation information in the brain.

Malformation of cortical development: the genesis of epileptogenic networks

Malformations of cortical development (MCDs) result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the genetic basis of MCDs have known prominent progress during the past decade, including the identification of somatic, mosaic mutations responsible for focal MCDs, the pathophysiological mechanisms linking malformations to epileptogenesis remain elusive. In this seminar I will present data from my team and from the literature addressing this topic in two different MCDs types, the subcortical band heterotopia as a model of cortical migration defect and mTOR- dependent MCDs , that characterize by cortical dyslamination and neuronal differentiation defects.

Dysregulation of mTOR Signaling Mediates Common Neurite and Migration Defects in Idiopathic and 16p11.2 Deletion Autism neural progenitors

Adult neurogenesis in mouse hippocampus

Dr. Aixa V. Morales has been working for more than 20 years in the field of Developmental Biology and from 2005, she is the PI of the laboratory on “Molecular Control of Neurogenesis” at Cajal Institute. Along these years, she has contributed to understanding the control of neurogenesis during development, the dorsoventral specification of neural progenitors, and the temporal control of the migration of neural crest cells. More recently, her lab interest moved towards understanding modulation of adult neurogenesis. Her lab current interest is the control of quiescence, as a mechanism of long-term neural stem cell maintenance in adult niches.

Sympathetic control of lymph node function

Peripheral nerve injury can cause debilitating disease and immune-cell mediated destruction of the affected nerve. While the focus of most studies has been on the nerve-degenerative response, the effect of loss of innervation on lymph node function is largely unclear. Here, I will discuss the cellular and molecular events caused by local denervation and loss of direct neural input to the popliteal lymph node that induce an inflammatory response and lymph node expansion.

Australian Bogong moths use a true stellar compass for long-distance navigation at night

Each spring, billions of Bogong moths escape hot conditions in different regions of southeast Australia by migrating over 1000 km to a limited number of cool caves in the Australian Alps, historically used for aestivating over the summer. At the beginning of autumn the same individuals make a return migration to their breeding grounds to reproduce and die. To steer migration Bogong moths sense the Earth’s magnetic field and correlate its directional information with visual cues. In this presentation, we will show that a critically important visual cue is the distribution of starlight within the austral night sky. By tethering spring and autumn migratory moths in a flight simulator, we found that under natural dorsally-projected night skies, and in a nulled magnetic field (disabling the magnetic sense), moths flew in their seasonally appropriate migratory directions, turning in the opposite direction when the night sky was rotated 180°. Visual interneurons in the moth’s optic lobe and central brain responded vigorously to identical sky rotations. Migrating Bogong moths thus use the starry night sky as a true compass to distinguish geographic cardinal directions, the first invertebrate known to do so. These stellar cues are likely reinforced by the Earth’s magnetic field to create a robust compass mechanism for long-distance nocturnal navigation.

All optical interrogation of developing GABAergic circuits in vivo

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring and programmed cell-death. But cortical GABAergic neurons are also specified by very early developmental programs. For example, the earliest born GABAergic neurons develop into hub cells coordinating spontaneous activity in hippocampal slices. Despite their importance for the emergence of sensory experience, their role in coordinating network dynamics, and the role of activity in their integration into cortical networks, the collective in vivo dynamics of GABAergic neurons during the neonatal postnatal period remain unknown. Here, I will present data related to the coordinated activity between GABAergic cells of the mouse barrel cortex and hippocampus in non-anesthetized pups using the recent development of all optical methods to record and manipulate neuronal activity in vivo. I will show that the functional structure of developing GABAergic circuits is remarkably patterned, with segregated assemblies of prospective parvalbumin neurons and highly connected hub cells, both shaped by sensory-dependent processes.

Vulnerable periods of brain development in ion channelopathies

Brain and neuronal network development depend on a complex sequence of events, which include neurogenesis, migration, differentiation, synaptogenesis, and synaptic pruning. Perturbations to any of these processes, for example associated with ion channel gene mutations (i.e., channelopathies), can underlie neurodevelopmental disorders such as neonatal and infantile epilepsies, strongly impair psychomotor development and cause persistent deficits in cognition, motor skills, or motor control. The therapeutic options available are very limited, and prophylactic therapies for patients at an increased risk of developing such epilepsies do not exist yet. By using genetic mouse models in which we controlled the activities of Kv7/M or HCN/h-channels during different developmental periods, we obtained offspring with distinct neurological phenotypes that could not simply be reversed by the re-introduction of the affected ion channel in juvenile or adult animals. The results indicate that channelopathy/mutation-specific treatments of neonatal and infantile epilepsies and their comorbidities need to be targeted to specific sensitive periods.

Microglia function and dysfunction in Alzheimer’s disease

Emerging genetic studies of late-onset Alzheimer’s Disease implicate the brain’s resident macrophages in the pathogenesis of AD. More than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells; yet we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis. Using single-cell RNA sequencing and spatial transcriptomics we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in the human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. We identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of Alzheimer’s disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.

Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis

Following neuronal trajectories

Malformations of the human cerebral cortex represent a major cause of developmental disabilities. To date, animal models carrying mutations of genes so far identified in human patients with brain malformations only partially recapitulate the expected phenotypes and therefore do not provide reliable models to entirely understand the molecular and cellular mechanisms responsible for these disorders. Hence, we combine the in vivo mouse model and the human brain organoids in order to better comprehend the mechanisms involved in the migration of neurons during human development and tackle the causes of neurodevelopmental disorders. Our results show that we can model human brain development and disorders using human brain organoids and contribute to open new avenues to bridge the gap of knowledge between human brain malformations and existing animal models.

Fate and freedom in developing neocortical circuits

During brain development, neurons are born in specialized niches and migrate to target regions where they assemble to form the circuits that underlie mammalian behaviour. During their journey, neurons follow cell-intrinsic, genetic programs transmitted by their mother cells but also environmental cues, which together drive their maturation. Here, focusing on the neocortex, I will discuss recent findings from our laboratory in which we untangle and manipulate the programs at play in progenitors and their daughter neurons to better understand the emergence of cellular diversity in the developing brain.

Activity-Dependent Network Development in Silico: The Role of Inhibition in Neuronal Growth and Migration

Bernstein Conference 2024

Spatial proteomics reveals distinct protein patterns in cortical migration disorders caused by LIN28A overexpression and WNT activation

FENS Forum 2024

Analysis of the regulation of cortical interneuron migration by the D1 receptor in the mouse

AQP4 expression level and aggregation state affect astrocyte migration in an in vitro model of reactive gliosis

The atypical kinesin Kif21b controls neuronal migration through regulation of actin contraction

Human-specific modifiers of the WASH complex control cortical neuron migration and fate specification

The DNA methyltransferase 1 is important for the migration of MGE-derived interneurons

Migration defects in Fragile X Syndrome

Migration-promoting vascular scaffold in the postnatal neurogenic region: a comparison of mice and rats

Molecular and physical factors coordinate Cajal-Retzius cells migration in the marginal zone during neocortical development

Novel missense mutations alter RELN function causing recessive and dominant Neuronal Migration Disorders

Primary cilium-elicited signalling pathways and cortical interneuron migration

Short- and long-distance extrinsic regulation of interneuron specification and migration

Study of mechanotransduction and migration behavior in a Krabbe disease cell model

Subthreshold activity may regulate the migration of cortical 5HT3aR-expressing interneurons

In vivo intratumoral calcium heterogeneity in Glioblastoma Multiforme correlates with migrational patterns

Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons

FENS Forum 2024

C-terminal binding protein 1 is necessary for normal migration of adult-born neurons

FENS Forum 2024

DNA damage during early neurogenesis impairs interneuron migration without altering their ultimate cortical positioning

FENS Forum 2024

Development of iPSC-derived neural progenitor cells with enhanced migration to stroke tissue and inducible ablation systems

FENS Forum 2024

Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions

FENS Forum 2024

Modelling the radial glia scaffold in vitro to study radial migration of pyramidal neurons

FENS Forum 2024

Novel lissencephaly-associated DCX variants affect microtubule binding, dynamics, and neuronal migration

FENS Forum 2024

Role of Na+/Ca2+ exchanger NCX in glioblastoma cell migration

FENS Forum 2024

Synergistic effect of melatonin and methylprednisolone on reducing disability in EAE by ameliorating induction, migration, and reactivation of T cells in the central nervous system

FENS Forum 2024