NOSELLI

Stéphane NOSELLI

Epithelial Morphogenesis and left-right asymmetry in Drosophila

Main interests

  • Mechanisms controlling Visceral and Brain Left-Right Asymmetry
  • Role of the conserved Myosin1D and of the Actin Cytoskeleton in LR Symmetry Breaking
  • Origin, Propagation and Evolution of Biological Chirality
  • Signaling Pathways controlling Collective Cell Migration

Scientific Questions

Emergence of Asymmetry from an initially symmetrical state is a universal transition in Nature. Living organisms show striking asymmetries at all scales (molecular, cellular, tissular, organismal) and one of their fundamental features lies in their assembly from homochiral molecular components. Whether the macroscopic asymmetries of living systems are directly related to their molecular chirality remains an open question. We study Left-Right Asymmetry in Drosophila to characterize the molecular basis of laterality and address the origin, propagation and evolution of symmetry breaking.

Tissue morphogenesis relies on another fundamental transition, the Immotile-to-Motile Transition, leading individual cells or groups of cells to undergo migration. The acquisition of motility by cancer cells leads them to become metastatic or invasive. Drosophila Border Cells represent a powerful paradigm to study collective cell migration in vivo. Using this system, we characterize the role of new genes and conserved signaling pathways controlling motility.

Our Strategy

Our research program aims at better understanding the mechanisms underlying symmetry breaking, and how this information is propagated to target cells and organs. We are also trying to understand how asymmetry can cross organizational layers to become multiscale (from molecular to behavioral) and whether these fundamental mechanisms are conserved during evolution. To these goals, we initiated the study of LR asymmetry in Drosophila. Our previous work identified Myosin1D as a unique situs inversus gene, regulating visceral LR asymmetry through cell death, E-Cadherin, HOX genes and the conserved PCP pathways. More recently, we have shown that Myo1D orthologs control LR asymmetry in both xenopus and zebrafish, revealing Myo1D as the first unifying principle of laterality across phyla.

Our current work aims at identifying new genes/pathways and concepts controlling asymmetry and motility, using multiscale approaches combining biochemistry, genetics, cell biology and modeling. More specifically, we design large-scale genetic and molecular screens to i) identify new genes controlling visceral LR asymmetry, ii) establish Drosophila as a new paradigm to study brain asymmetry and iii) identify new genes involved in the control of cell motility in vivo.

Research Aims

VISCERAL LR ASYMMETRY is controlled by the conserved Myosin1D protein which is active in multiple and independent LR organizers. In these, Myo1D sets and propagates asymmetry to individual organs (genitalia, hindgut, etc.), each of them having their own morphogenetic program. We are currently deciphering the core asymmetry pathway, the mode(s) of information propagation as well as downstream morphogenetic programs by i) characterizing new genes involved in the Myo1D pathway, ii) studying the interaction between the Myo1D and PCP pathways, iii) determining the role of the actin cytoskeleton in the process.

BRAIN LR ASYMMETRY is essential for a number of cognitive and behavioral processes, yet the mechanisms controlling nervous system asymmetry are poorly understood. Of note, brain and visceral asymmetry are mostly controlled by specific programs. We are currently initiating the study of nervous system LR asymmetry in Drosophila through large-scale genetic screening and functional characterization. Our recent results allowed the identification of the first genes and mechanisms underlying brain asymmetry in flies. The role of gene orthologs will be studied in the vertebrate nervous system.

CELL MOTILITY is a complex, multistep process involving communication with neighboring tissues and the environment. Transition from an immotile to a motile phenotype depends on the regulation of cell adhesion, polarity, growth and signalling. To understand how cohorts of cells migrate in a coordinated manner, we are identifying and characterizing new regulators of Border Cell migration during Drosophila oogenesis.

Researchers

GHIGLIONE Christian - +33 489150751
VAN DE BOR Véronique - +33 489150753
BANRETI Agnès - +33 489150752

PreDocs

RAVEL Nils - +33 R

Engineers & Technicians

CEREZO Delphine - +33 489150752
LAPRAZ François - +33 489150753
BOUTRES Céline - +33 489150753
FIXARY-SCHUSTER Cloé - +33 489150752

 

Recent publications

  1. Fixary-Schuster, C, Lapraz, F, Noselli, S. [Netrin signaling pathway, memory and brain lateralization]. Med Sci (Paris). 2024;40 (2):139-142. doi: 10.1051/medsci/2023209. PubMed PMID:38411419 .
  2. Lapraz, F, Boutres, C, Fixary-Schuster, C, De Queiroz, BR, Plaçais, PY, Cerezo, D et al.. Asymmetric activity of NetrinB controls laterality of the Drosophila brain. Nat Commun. 2023;14 (1):1052. doi: 10.1038/s41467-023-36644-4. PubMed PMID:36828820 PubMed Central PMC9958012.
  3. Banreti, A, Bhattacharya, S, Wien, F, Matsuo, K, Réfrégiers, M, Meinert, C et al.. Biological effects of the loss of homochirality in a multicellular organism. Nat Commun. 2022;13 (1):7059. doi: 10.1038/s41467-022-34516-x. PubMed PMID:36400783 PubMed Central PMC9674851.
  4. Van De Bor, V, Loreau, V, Malbouyres, M, Cerezo, D, Placenti, A, Ruggiero, F et al.. A dynamic and mosaic basement membrane controls cell intercalation in Drosophila ovaries. Development. 2021;148 (4):. doi: 10.1242/dev.195511. PubMed PMID:33526583 .
  5. Chougule, A, Lapraz, F, Földi, I, Cerezo, D, Mihály, J, Noselli, S et al.. The Drosophila actin nucleator DAAM is essential for left-right asymmetry. PLoS Genet. 2020;16 (4):e1008758. doi: 10.1371/journal.pgen.1008758. PubMed PMID:32324733 PubMed Central PMC7200016.
  6. Rice, G, David, JR, Kamimura, Y, Masly, JP, Mcgregor, AP, Nagy, O et al.. A standardized nomenclature and atlas of the male terminalia of Drosophila melanogaster. Fly (Austin). 2019;13 (1-4):51-64. doi: 10.1080/19336934.2019.1653733. PubMed PMID:31401934 PubMed Central PMC6988887.
  7. Lebreton, G, Géminard, C, Lapraz, F, Pyrpassopoulos, S, Cerezo, D, Spéder, P et al.. Molecular to organismal chirality is induced by the conserved myosin 1D. Science. 2018;362 (6417):949-952. doi: 10.1126/science.aat8642. PubMed PMID:30467170 PubMed Central PMC6698710.
  8. Ghiglione, C, Jouandin, P, Cérézo, D, Noselli, S. The Drosophila insulin pathway controls Profilin expression and dynamic actin-rich protrusions during collective cell migration. Development. 2018;145 (14):. doi: 10.1242/dev.161117. PubMed PMID:29980565 .
  9. Juan, T, Géminard, C, Coutelis, JB, Cerezo, D, Polès, S, Noselli, S et al.. Myosin1D is an evolutionarily conserved regulator of animal left-right asymmetry. Nat Commun. 2018;9 (1):1942. doi: 10.1038/s41467-018-04284-8. PubMed PMID:29769531 PubMed Central PMC5955935.
  10. Tingler, M, Kurz, S, Maerker, M, Ott, T, Fuhl, F, Schweickert, A et al.. A Conserved Role of the Unconventional Myosin 1d in Laterality Determination. Curr Biol. 2018;28 (5):810-816.e3. doi: 10.1016/j.cub.2018.01.075. PubMed PMID:29478852 .
  11. Roumengous, S, Rousset, R, Noselli, S. Polycomb and Hox Genes Control JNK-Induced Remodeling of the Segment Boundary during Drosophila Morphogenesis. Cell Rep. 2017;19 (1):60-71. doi: 10.1016/j.celrep.2017.03.033. PubMed PMID:28380363 .
  12. Rousset, R, Carballès, F, Parassol, N, Schaub, S, Cérézo, D, Noselli, S et al.. Signalling crosstalk at the leading edge controls tissue closure dynamics in the Drosophila embryo. PLoS Genet. 2017;13 (2):e1006640. doi: 10.1371/journal.pgen.1006640. PubMed PMID:28231245 PubMed Central PMC5344535.
  13. Van De Bor, V, Zimniak, G, Papone, L, Cerezo, D, Malbouyres, M, Juan, T et al.. Companion Blood Cells Control Ovarian Stem Cell Niche Microenvironment and Homeostasis. Cell Rep. 2015;13 (3):546-560. doi: 10.1016/j.celrep.2015.09.008. PubMed PMID:26456819 .
  14. González-Morales, N, Géminard, C, Lebreton, G, Cerezo, D, Coutelis, JB, Noselli, S et al.. The Atypical Cadherin Dachsous Controls Left-Right Asymmetry in Drosophila. Dev Cell. 2015;33 (6):675-89. doi: 10.1016/j.devcel.2015.04.026. PubMed PMID:26073018 .
  15. Coutelis, JB, González-Morales, N, Géminard, C, Noselli, S. Diversity and convergence in the mechanisms establishing L/R asymmetry in metazoa. EMBO Rep. 2014;15 (9):926-37. doi: 10.15252/embr.201438972. PubMed PMID:25150102 PubMed Central PMC4198036.
  16. Jouandin, P, Ghiglione, C, Noselli, S. Starvation induces FoxO-dependent mitotic-to-endocycle switch pausing during Drosophila oogenesis. Development. 2014;141 (15):3013-21. doi: 10.1242/dev.108399. PubMed PMID:24993942 PubMed Central PMC6514422.
  17. Géminard, C, González-Morales, N, Coutelis, JB, Noselli, S. The myosin ID pathway and left-right asymmetry in Drosophila. Genesis. 2014;52 (6):471-80. doi: 10.1002/dvg.22763. PubMed PMID:24585718 .
  18. Parassol, N, Bienvenu, C, Boglio, C, Fiorucci, S, Cerezo, D, Yu, XM et al.. In vivo characterization of dynein-driven nanovectors using Drosophila oocytes. PLoS One. 2013;8 (12):e82908. doi: 10.1371/journal.pone.0082908. PubMed PMID:24349395 PubMed Central PMC3861458.
  19. Coutelis, JB, Géminard, C, Spéder, P, Suzanne, M, Petzoldt, AG, Noselli, S et al.. Drosophila left/right asymmetry establishment is controlled by the Hox gene abdominal-B. Dev Cell. 2013;24 (1):89-97. doi: 10.1016/j.devcel.2012.11.013. PubMed PMID:23328400 .
  20. De Graeve, FM, Van de Bor, V, Ghiglione, C, Cerezo, D, Jouandin, P, Ueda, R et al.. Drosophila apc regulates delamination of invasive epithelial clusters. Dev Biol. 2012;368 (1):76-85. doi: 10.1016/j.ydbio.2012.05.017. PubMed PMID:22627290 .
Search PubMed

Projet de thèse avec bourse, au sein de l’équipe de Stéphane Noselli à l’institut de Biologie Valrose’ (iBV), Université Côte d’Azur à Nice, FR.

Asymétrie droite-gauche et système nerveux : nouveaux gènes, nouvelles fonctions

L’asymétrie Droite-Gauche (DG) joue un rôle central dans l’organisation (positionnement, morphologie) et la fonction de nombreux organes (par ex : coeur, cerveau). Chez l’Homme, des défauts d’asymétrie DG des organes viscéraux entrainent de nombreuses malformations ou syndromes (situs inversus, malformation cardiaque, asplénie, syndromes de Kartagener, Ivemark, etc.), qui sont souvent associés à des maladies ciliaires et responsables d’un grand nombre de fausses-couches.

Le système nerveux présente également des asymétries DG à divers niveaux : anatomique, connectique (réseaux de connections neurales), et fonctionnel (comportements latéralisés, par ex. préférence main droite/gauche, et processus cognitifs complexes comme la mémoire). Illustrant son importance fonctionnelle chez l’homme, plusieurs troubles et syndromes sont fortement corrélés à des défauts de latéralité du système nerveux : Autisme, Schizophrénie, Hyperactivité et déficit d’attention, dyslexie etc.

De façon surprenante et intéressante, l’asymétrie des organes viscéraux et du cerveau est contrôlée par des mécanismes indépendants. Si les mécanismes contrôlant l’asymétrie des organes viscéraux est bien connue, nous ne savons en revanche rien de ceux contrôlant l’asymétrie du système nerveux, tant chez les mammifères que chez les invertébrés.

Notre projet vise à élucider les mécanismes d’asymétrie du système nerveux en utilisant le modèle drosophile, qui offre de très nombreux avantages méthodologiques. Par ailleurs, Il est estimé que 75% des gènes ayant un lien avec une maladie chez l’homme ont un équivalent chez la Drosophile. Mieux comprendre le contrôle génétique et la fonction des asymétries chez la Drosophile permettra la mise en évidence de mécanismes inédits conservés chez les vertébrés dont l’homme.

Notre laboratoire est pionnier dans l’étude de l’asymétrie DG chez le modèle drosophile. Le projet s’intéressera dans un premier temps à un circuit de neurones asymétriques présent uniquement du côté droit. De manière intéressante, ce circuit met en lumière chez la Drosophile l’existence, comme chez les vertébrés, d’un lien direct entre asymétrie cérébrale et cognition. En effet, une perte d’asymétrie de ce circuit neuronal provoque des défauts de mémoire à long terme.

Le laboratoire a entrepris un crible RNAi à grande échelle et identifié récemment les premiers gènes connus à ce jour affectant la mise en place de cette asymétrie chez la Drosophile. Les gènes et voies de signalisation identifiés sont fortement conservés chez l’homme. Le projet consistera à exploiter les nombreuses ressources et outils génétiques disponibles pour analyser le rôle des gènes/voies identifiés, en : 1) Caractérisant les défauts d’asymétries causés par les mutations, 2) Identifiant le réseau génique, le mécanisme d’action et les partenaires des gènes candidats, 3) Caractérisant le réseau neuronal impliqué et les défauts comportementaux/cognitifs provoqués par une altération de leur asymétrie, 4) Etudiant le rôle des gènes homologues dans le système nerveux de vertébrés modèles, en collaboration avec des laboratoires experts avec lesquels nous travaillons.

Ce projet pionnier débouchera sur la caractérisation des premiers gènes impliqués dans le contrôle de l’asymétrie du système nerveux et des fonctions cognitives associées.

Une large panoplie de techniques de laboratoire sera utilisée, incluant l’imagerie (microscopie confocale, 2-photon, reconstruction 3D de réseaux de neurones, etc.), la génétique (mendélienne, CRISPR, RNAi), expression contrôlée dans le temps et l’espace (système Gal4/UAS), toutes les techniques de biologie moléculaire et cellulaire, modélisation, etc..

 

N’hésitez pas à contacter le laboratoire pour de plus amples informations :

ibv.unice.fr/research-team/noselli

Stéphane Noselli : noselli@unice.fr
François Lapraz : lapraz@unice.fr

L‘institut de Biologie Valrose’ iBV, (28 équipes ; 310 personnes ; 25 nationalités) est un institut de recherche reconnu au niveau international disposant d’un environnement scientifique riche et dynamique, de nombreuses plateformes technologiques modernes et une atmosphère de travail collaborative et attractive. (ibv.unice.fr)

 

Selected Publications

Spéder et al., Nature 2006
Gettings et al., PLoS Biol 2010
Suzanne et al., Cur Biol 2010
Petzoldt et al., Development 2012
Coutelis et al., Dev Cell 2013
Géminard et al., Genesis 2014
Coutelis et al., EMBO Reports 2014
Gonzales-Morales et al., Dev Cell 2015
Van de Bor et al., Cell Reports 2015
Rousset et al., PLoS Genetics 2017
Roumengous et al., Cell Reports 2017
Juan et al, Nature Communications 2018
Tingler et al., Current Biology 2018
Ghiglione et al., Development 2018

A 3-year postdoctoral position is available in the group of Dr Stéphane NOSELLI at the ‘institut de Biologie Valrose’ (iBV), Université Côte d’Azur in Nice, FR.

Our lab investigates the origin of biological chirality and the role of the actin cytoskeleton and associated myosins (type I myosins) in this fundamental property. We approach this problem by studying how Left-Right asymmetry is established in Drosophila, using multidisciplinary approaches addressing a number of primary questions: How is symmetry breaking taking place? What are the molecular determinants of asymmetry/chirality? How molecular chirality translates into higher order organ asymmetry, bridging different
biological scales? How is the Myosin I system conserved during evolution?
This project aims at characterizing the role of the actin cytoskeleton in LR symmetry breaking and asymmetric morphogenesis, and its interaction with actin-associated factors that we have recently identified through genetic screening.

Highly motivated candidates with original thinking and background in Developmental Biology, Cell Biology, Biochemistry are encouraged to apply. Previous experience in actin/cytoskeleton biology would be a plus.
Interested candidates can contact S. Noselli (noselli@unice.fr).

The ‘institut de Biologie Valrose’ (27 teams; 300 persons; 25 nationalities) is an international institute (English is the working language) with a rich and vivid scientific environment. iBV provides state of the art core facilities, with a collaborative and lively atmosphere in a gorgeous city/region. (ibv.unice.fr/EN/index.php)

Selected publications:
Speder et al., Nature 2006
Gettings et al., PLoS Biol 2010
Suzanne et al., Cur Biol 2010
Petzoldt et al., Development 2012
Coutelis et al., Dev Cell 2013
Géminard et al., Genesis 2014
Coutelis et al., EMBO Reports 2014
Gonzales-Morales et al., Dev Cell 2015
Van de Bor et al., Cell Reports 2015
Rousset et al., PLoS Genetics 2017
Roumengous et al., Cell Reports 2017

2018 - Elected Member of Academia Europaea

2014  - CNRS Research Director - Exceptional Class

2014 - EMBO Member - EMBO

2013 - Grand Prix Mottart - Académie des Sciences

2008 - Excellence Award (Prime d'excellence Scientifique) - CNRS

2008 - Team FRM

2008 - Silver Medal - CNRS

2007  - "Grandes Avancées Françaises en Biologie" - French Academy of Sciences

2001 - Young Investigator Program - EMBO

1999 - ATIP Developmental Biology - CNRS

1998 - Bronze Medal - CNRS

Congratulations to Yasmine Neirijnck and Agnes Banreti for their INSERM permanent positions!

Yasmine Neirijnck and Agnes Banreti were both recruited by INSERM this year as permanent researchers at the iBV. We asked ...
Read More

UCA annual Award Ceremony: 7 iBV members recognised for their scientific contributions

iBV is a member of Université Cote d’Azur (UCA), a cluster of Research and Higher Education on the French Riviera. Each ...
Read More

The origins of asymmetry: A protein that makes you do the twist

Asymmetry plays a major role in biology at every scale: think of DNA spirals, the fact that the human heart ...
Read More

Stéphane NOSELLI is elected Member of Academia Europaea

Stéphane NOSELLI, Director of the ‘institut de Biologie Valrose (iBV)’ (UCA, UNS, CNRS, Inserm), has been elected a member of ...
Read More

iBV - Institut de Biologie Valrose

"Centre de Biochimie"

Université Nice Sophia Antipolis
Faculté des Sciences
Parc Valrose
06108 Nice cedex 2