Developmental Biology Institute of Marseille

Stem cells and brain repair

The team focuses on the process of post-lesional plasticity following demyelination in the adult brain. In some patients affected by multiple sclerosis (MS) spontaneous remyelination can occur. Although insufficient to counter the damages caused by the repetitive attacks, this spontaneous regenerative process represent great therapeutic hopes. Studies led on rodent have identified two distinct sources of cells involved in remyelination: the oligodendrocyte progenitors (OPCs) found throughout the brain parenchyma and neural progenitor derived from the sub-ventricular zone (SVZ) were adult neural stem cells reside.

Our objectives are to uncover the cellular and molecular mechanisms controlling this process in order to increase our fundamental knowledge on brain regeneration and to promote myelin repair.

Cellular interactions, neurodegeneration and neuroplasticity

The team studies cellular interactions and neuroplasticity in the adult brain, in particular in the context of basal ganglia-related functions and pathologies.

Ongoing projects are centered on the pathophysiology and treatment of Parkinson’s disease and the role of glutamatergic systems.

Our approach combines the use or development of relevant experimental models in rodents (chronic deep brain stimulation, genetic model of cell specific ablation, optogenetic modulation of neuronal activity) with a variety of analytic tools including functional anatomy, electrophysiology (in vitro and in vivo), neurochemistry and molecular/cellular biology.

Chronic pain: molecular and cellular mechansims

Our team aims at understanding how primary sensory neurons diversity is translated at the functional level. To do this we use state-of-the-art technologies combining mouse genetics, transcriptomic analyses, molecular and cellular biology, electrophysiology and behavior.  In the last few years we successfully contributed to extend our understanding of the molecular logic that governs nociceptive neurons diversity, we unraveled the functional role of newly identified genes in pain biology and deciphered the functional specialization of two newly characterized subpopulations of primary sensory neurons. Currently, our projects are heading towards a better understanding of the circuitry between primary sensory neurons and spinal cord neuronal networks. We are also developing clinically-driven projects in which we investigate the molecular and cellular mechanisms that underlie the transition from acute to chronic pain.

Polarization and binary cell fate decisions in the nervous system

In both vertebrates and invertebrates, postmitotic neurons are often generated by asymmetric divisions of neuronal progenitors such as neural stem cells. This general mechanism used to build the nervous system raises two important questions : how are these asymmetric divisions coordinated in space and how do the daughter cells acquire different fates.

We address these questions using the nematode C. elegans as a model organism. In C. elegans, most neurons are generated during neurulation by asymmetric divisions oriented along the antero-posterior axis. We recently showed that these terminal asymmetric divisions are regulated by a particular Wnt/β-catenin pathway. We are now trying to understand :

1) How the field of neuronal precursors is polarized.

2) How the daughter cells acquire different fates and especially how the asymmetric division machinery is connected to the terminal differentiation program of postmitotic neurons.

The Wnt/β-catenin pathway is involved in several types of cancer and in the regulation of asymmetric divisions of neural stem cells in vertebrates. This study may therefore help identify candidate target proteins and mechanisms for future anti-cancer drug developments or regenerative medicine treatments.

Molecular control of neurogenesis

How are neural stem cells determined to generate neurons with defined neurotransmitter phenotypes? How do neurons migrate to their final positions? How are neurons synaptically integrated into the circuitry and what is their physiological function?

We use postnatal olfactory bulb neurogenesis to identify and functionally characterize factors and signaling cascades that regulate these processes. To reach this aim we combine high-resolution gene expression screens with mouse genetics and state-of-the-art in vivo brain imaging by multiphoton microscopy.

Transcriptional regulatory network in development and diseases

Teashirt3 (TSHZ3) is a zinc finger transcription factor whose targets and functional implications remain largely unknown. Our previous studies support that Tshz3 plays a role in the developing and maturing cerebral cortex. To unravel the role of Tshz3 in the development and function of cortical projection systems, we are characterizing novel mouse models of Tshz3 deletion by combining mouse genetics, molecular biology, morphological and tract tracing studies, slice electrophysiology and behavioral approaches. This research will improve our knowledge on mechanisms underlying early corticogenesis and/or maturation and functioning of cortical circuits.

Development and pathologies of neuromuscular circuits

The Helmbacher team studies neuromuscular development and pathology. Our research aims to understand processes that control the development of neuromuscular circuits, and to uncover how alterations of these developmental processes lead to devastating neuromuscular pathologies in human. Our work on neuromuscular development integrates the study of cell fate diversity and the mutual dependency of motor neurons and their target muscles. We aim to identify the signals successively exchanged by neurons and muscles during development, such as the signals acting on neuronal and muscular specification, the signals that pattern neural projections through axonal guidance and through muscle morphogenesis, the signals that regulate homogeneous growth and match the size of neuromuscular units. We study how all these signals successfully integrate to produce locomotor activity.

Our work recently uncovered the link between a human myopathy, Facioscapulohumeral dystrophy, and genetic alterations of the FAT1 cadherin gene, a gene involved in neuromuscular development. We currently work at determining the contribution of FAT1-dependent phenotypes to FSHD-like muscular symptoms. Besides, we also explore how FAT/Dachsous cadherin signaling contributes to the functional maturation of neuromuscular circuitry.

Signalling networks for stemness and tumorigenesis

We aim at uncovering how convergent instructive signals cooperate to regulate the fate of cells. This question is addressed by using two biological contexts: the transition of healthy cells towards tumorigenesis and the regulation of self-renewal versus differentiation of stem cells.

Concerning stem cells, the team studies how human induced pluripotent stem cells (iPSCs) fine-tune perception of instructive extracellular signals in order to: 1) enhance generation of functional neurons (e.g. dopaminergic neurons) both in vitro and in vivo; 2) improve safety of human iPSC-derived cell grafts in animal models of neurodegenerative disorders (e.g. Parkinson’s disease) by preventing tumour side effects.

Our objective is to acquire knowledge on human iPSC biology related to neural/neuronal differentiation by exploring molecular and signalling networks. This research may open new perspectives in regenerative medicine by developing more effective, user-friendly, and safe stem cell-based therapeutic strategies (project leader Dr Rosanna Dono).

Axon plasticity in development and cancer

Normal brain function depends on complex patterns of neuronal circuits that develop during fetal life and childhood. Neurons connect to each other by extending long cables, called axons, whose growth is not random but precisely oriented towards their targets by axon guidance molecules. Our team studies the mechanisms that contribute to the fine regulation of guidance cue activities to ensure the accuracy and fidelity of axonal trajectories.

In addition to being essential to brain development, axon guidance molecules are also present in adult organisms where their expression can be reactivated under pathological conditions such as cancer. We are investigating whether their activity could contribute to the innervation of malignant tumors, a process that is still poorly characterized but can influence the course of the disease.

Neural stem cell plasticity

Neural stem cells found in the nervous system are very plastic. This plasticity allows them to generate a vast repertoire of neural and glial progeny while the brain is being built or to regenerate neurons after brain injury. Our team aims at deciphering the molecular and genetic mechanisms underlying this plasticity. We are also investigating how environmental conditions during fetal growth affect neural stem cell plasticity and their ability to constitute their full repertoire of neurons. Finally, because of their plasticity and large proliferation potential, stem cells are largely exposed to cancer-promoting defects. Our ambition therefore consists in uncovering how neural stem cell plasticity can be hijacked for the benefit of cancerous processes. Understanding these basic principles could help correcting cellular failures responsible for cancer induction, delaying ageing and exploiting neural stem cell regenerative potential.

In order to investigate these fascinating issues, we use the fruitfly Drosophila. As in mammals, the Drosophila adult brain is mainly composed of neurons and glial cells (>100,000) disposed in complex neural circuits. These cells have been generated in the developing animal from a limited set of neural stem cells. We take advantage of the powerful genetic tools developed in this model organism to manipulate neural stem cells while the brain is being constructed during development. We aim at identifying the genes and molecular mechanisms controlling their properties.

Effects of gut microbiota on host behavior

The intestinal microbiota is composed of bacteria whose nature depends on the intestinal environment and the food preference of the host. In return, the microbiota manipulates the host by producing nutrients and excreting metabolites that modulate its physiology. If it is established that the microbiota regulates basal metabolism or educates the host’s immune system, recent results attest to its influence on the nervous system. Anxiety, depression, autism,… the microbiota modulates our behavior, regulates our emotions and intervenes in certain pathologies of the nervous system. If some of the mechanisms of host-microbiota communication have been elucidated, the field of investigation remains vast.

Thanks to the power of its genetics and the relative simplicity of its microbiota, Drosophila represents a promising alternative to mammalian models. Our results show that a bacterial component called peptidoglycan (PGN) is a key mediator in this dialogue. Under certain circumstances, PGN can cross the intestinal epithelium and reach the circulating blood in which organs and tissues are bathed. Our work has shown that the detection of this microbiota derived-PGN modulates the activity of certain octopaminergic neurons and ultimately the behavior of the host. Our team seeks to dissect the mechanistic details of this molecular dialogue between the microbiota and the host nervous system.

Evolution and Development of morphology and behavior