Development and Function of Brain Circuits
- COUP-TFI/NR2F1 in neurodevelopmental cortical disorders
- Transcriptional regulation and activity-dependent mechanisms during mammalian circuit formation
- Mechanisms controlling topographic neuronal connectivity
- Mapping neuronal populations involved in sensorimotor auditory circuits
During neurogenesis, different progenitor and neuronal cell types are sequentially generated from a complex population of multipotent stem cells following a precise spatial and temporal pattern before being assembled into maps and circuits. We aim to dissect the cellular and molecular mechanisms by which these different cell types are regulated by defined regionalized and coordinated intrinsic programs and by extrinsic activity-dependent cues that continuously interact during pre- and postnatal development, and control neuronal traits and topographic map formation.
We work on two major regions of the mouse brain: the forebrain and the hindbrain. In the forebrain, we focus on the transcriptional regulator COUP-TFI/NR2F1 recently identified as a neurodevelopmental disease gene and playing multiple roles during neocortical and hippocampal development. In the hindbrain, we aim to identify the different subpopulations arising from rhombomere 4 and contributing to the assembly of the central auditory, trigeminal and vestibular systems.
Fig. 1 – Embryonic mouse cortex labeled with cell-type specific antibodie
To unravel some of the key molecular and cellular mechanisms underlying neural organization and circuit formation, we use the mouse as an in vivo experimental model and several genetic mutants, which reproduce the clinical features of patients with either intellectual disabilities or hearing sensory impairments. Our strategy is to study the specification of progenitor and neuronal cell types as well as the assembly of neuronal circuits required in shaping distinct functional topographic maps in the healthy and diseased brain.
The team has added to the standard molecular and cellular approaches a whole series of interdisciplinary experimental techniques. We combine genetic gain-and-loss of function approaches, in utero electroporation, 3D imaging of axonal tracts, lineage tracing, in-depth morphological analysis, mouse behavior and high-throughput molecular screening to elucidate how cell specification, migration and connectivity are functionally coordinated and ensure proper assembly of subcircuits in the developing brain. We also aim to develop cerebral 3D organoids as an in vitro model of human development and disease with the overall goal to assess mutations identified in patients.
As developmental abnormalities participate in the etiology of several neuropsychiatric disorders, understanding how different brain populations become organized and connected is essential to advance our comprehension of cognitive human diseases.
Neurodevelopmental diseases arise from anomalies occurring during the embryonic or fetal age and impairing normal brain functioning. Haploinsufficiency of the orphan nuclear receptor COUP-TFI/NR2F1 leads to developmental delay, intellectual disability, autistic behavior, infantile epilepsy and optic atrophy. We are using different mouse models, in utero electroporation and in vitro approaches to understand the contribution of single mutations identified in patients in the pathophysiological mechanisms of this newly genetic rare disease.
Fig. 3 – Electroporated mouse brain
Transcriptional regulation and activity-dependent mechanisms are essential in the maturation of neurons and formation of complex neuronal networks. We are interested in understanding their contribution in the topographic connectivity between the cortex and their subcerebral targets. We focus on the molecular cascade required in driving layer V projection neurons into corticopontine or corticospinal motor neurons, and in remodeling layer IV neurons during the formation of primary somatosensory maps.
Fig. 4 – Thy1-eYFP-H transgenic line
Through functional and intersectional mouse genetics, we aim to map auditory pathways and networks in normal and pathological hearing conditions as well as to identify novel genes involved in the specification of auditory subtypes in the central nervous system. In particular, we will investigate how cells originating from distinct subdomains of rhombomere 4 (r4) contribute in shaping coordinated functional sensorimotor auditory subcircuits.
Fig. 5 - Rhombomere 4 fate map
- Del Pino, I, Tocco, C, Magrinelli, E, Marcantoni, A, Ferraguto, C, Tomagra, G et al.. COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex. Cereb Cortex. 2020;30 (11):5667-5685. doi: 10.1093/cercor/bhaa137. PubMed PMID:32572460 .
- Bertacchi, M, Romano, AL, Loubat, A, Tran Mau-Them, F, Willems, M, Faivre, L et al.. NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients. EMBO J. 2020;39 (13):e104163. doi: 10.15252/embj.2019104163. PubMed PMID:32484994 PubMed Central PMC7327499.
- Bertacchi, M, Gruart, A, Kaimakis, P, Allet, C, Serra, L, Giacobini, P et al.. Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome. EMBO Mol Med. 2019;11 (8):e10291. doi: 10.15252/emmm.201910291. PubMed PMID:31318166 PubMed Central PMC6685104.
- Mercurio, S, Serra, L, Motta, A, Gesuita, L, Sanchez-Arrones, L, Inverardi, F et al.. Sox2 Acts in Thalamic Neurons to Control the Development of Retina-Thalamus-Cortex Connectivity. iScience. 2019;15 :257-273. doi: 10.1016/j.isci.2019.04.030. PubMed PMID:31082736 PubMed Central PMC6517317.
- Contesse, T, Ayrault, M, Mantegazza, M, Studer, M, Deschaux, O. Hyperactive and anxiolytic-like behaviors result from loss of COUP-TFI/Nr2f1 in the mouse cortex. Genes Brain Behav. 2019;18 (7):e12556. doi: 10.1111/gbb.12556. PubMed PMID:30653836 .
- Terrigno, M, Bertacchi, M, Pandolfini, L, Baumgart, M, Calvello, M, Cellerino, A et al.. The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation. Stem Cell Reports. 2018;11 (3):756-769. doi: 10.1016/j.stemcr.2018.08.002. PubMed PMID:30174317 PubMed Central PMC6135738.
- Simi, A, Studer, M. Developmental genetic programs and activity-dependent mechanisms instruct neocortical area mapping. Curr Opin Neurobiol. 2018;53 :96-102. doi: 10.1016/j.conb.2018.06.007. PubMed PMID:30005291 .
- Bonzano, S, Crisci, I, Podlesny-Drabiniok, A, Rolando, C, Krezel, W, Studer, M et al.. Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo. Cell Rep. 2018;24 (2):329-341. doi: 10.1016/j.celrep.2018.06.044. PubMed PMID:29996095 .
- Ruiz-Reig, N, Andres, B, Lamonerie, T, Theil, T, Fairén, A, Studer, M et al.. The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala. Brain Struct Funct. 2018;223 (7):3279-3295. doi: 10.1007/s00429-018-1687-0. PubMed PMID:29869132 .
- Bertacchi, M, Parisot, J, Studer, M. The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease. Brain Res. 2019;1705 :75-94. doi: 10.1016/j.brainres.2018.04.024. PubMed PMID:29709504 .
- Ruiz-Reig, N, Studer, M. Rostro-Caudal and Caudo-Rostral Migrations in the Telencephalon: Going Forward or Backward?. Front Neurosci. 2017;11 :692. doi: 10.3389/fnins.2017.00692. PubMed PMID:29311773 PubMed Central PMC5742585.
- Odelin, G, Faure, E, Coulpier, F, Di Bonito, M, Bajolle, F, Studer, M et al.. Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Development. 2018;145 (1):. doi: 10.1242/dev.151944. PubMed PMID:29158447 .
- Parisot, J, Flore, G, Bertacchi, M, Studer, M. COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression. Development. 2017;144 (11):2045-2058. doi: 10.1242/dev.139949. PubMed PMID:28506990 .
- Di Bonito, M, Studer, M, Puelles, L. Nuclear derivatives and axonal projections originating from rhombomere 4 in the mouse hindbrain. Brain Struct Funct. 2017;222 (8):3509-3542. doi: 10.1007/s00429-017-1416-0. PubMed PMID:28470551 PubMed Central PMC5676809.
- Di Bonito, M, Studer, M. Cellular and Molecular Underpinnings of Neuronal Assembly in the Central Auditory System during Mouse Development. Front Neural Circuits. 2017;11 :18. doi: 10.3389/fncir.2017.00018. PubMed PMID:28469562 PubMed Central PMC5395578.
- Glasco, DM, Pike, W, Qu, Y, Reustle, L, Misra, K, Di Bonito, M et al.. The atypical cadherin Celsr1 functions non-cell autonomously to block rostral migration of facial branchiomotor neurons in mice. Dev Biol. 2016;417 (1):40-9. doi: 10.1016/j.ydbio.2016.07.004. PubMed PMID:27395006 PubMed Central PMC5007083.
- Tonchev, AB, Tuoc, TC, Rosenthal, EH, Studer, M, Stoykova, A. Zbtb20 modulates the sequential generation of neuronal layers in developing cortex. Mol Brain. 2016;9 (1):65. doi: 10.1186/s13041-016-0242-2. PubMed PMID:27282384 PubMed Central PMC4901408.
- Touzot, A, Ruiz-Reig, N, Vitalis, T, Studer, M. Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain. Development. 2016;143 (10):1753-65. doi: 10.1242/dev.131102. PubMed PMID:27034423 .
- Harb, K, Magrinelli, E, Nicolas, CS, Lukianets, N, Frangeul, L, Pietri, M et al.. Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications. Elife. 2016;5 :e09531. doi: 10.7554/eLife.09531. PubMed PMID:26814051 PubMed Central PMC4744182.
- Flore, G, Di Ruberto, G, Parisot, J, Sannino, S, Russo, F, Illingworth, EA et al.. Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis. Cereb Cortex. 2017;27 (2):1629-1643. doi: 10.1093/cercor/bhv336. PubMed PMID:26813976 .
Postdoctoral position in Developmental Neurobiology
A postdoctoral position is available from January 2021 in the “Development and Function of Brain Circuits” team led by M. Studer. We aim to understand how rare genetic variants of key master genes of brain development and circuit assembly can cause neurodevelopmental diseases (NDDs). The project will determine the impact of missense variants identified in the NR2F1 gene on the heterogeneity of neurodevelopmental defects described in affected patients. The postdoc will study genotype/phenotype correlations by using CRISPR/Cas9 gene editing in vivo and decipher the
pathological contribution of representative variants in the mouse system. We expect that the results of this work using experimental systems as well as the identification of Nr2f1 direct targets and interacting partners will help in understanding the phenotypic heterogeneity of patients and unveil pathophysiological mechanisms common to multiple NDDs.
The team is located in the heart of Nice and is part of the Institute of Biology Valrose (27 teams; 300 people; 25 nationalities), an international research centre that brings together high-profile teams with complementary areas of expertise and with a common interest in translating basic research into knowledge for the clinic. The iBV provides state of the art core facilities, with a collaborative and lively atmosphere in a gorgeous city/region. For more information, visit http://ibv.unice.fr/institute/presentation/
Qualification and experience
We are seeking highly motivated young candidates holding a PhD for less than 2 years. Preference will be given to applicants with a background in mouse genetics, cellular and molecular biology, confocal imaging and genome wide approaches. The position is opened for one year renewable up to 3 years (including medical benefits) starting as early as January 2021. Fluency in English is mandatory but ability to speak French is not required.
Applications should contain a CV, a letter of motivation with a description of research accomplishments (2 pages max) and the contact information of two references able to recommend their research work directly to Michele.STUDER@unice.fr.
Selected related publications :
1. Bertacchi M. et al., EMBO J. 2020 Jun 2. PMID: 32484994
2. Bertacchi M. et al., EMBO Mol Med. 2019 Jul 18. PMID: 31318166
3. Bertacchi M. et al., Review, Brain Res. 2018, Apr 27. PMID: 29709504.
4. Bosch D.G.et al., Am J Hum Genet 2014, Feb 6.. PMID: 24462372
2015 - Equipe labélisée - FRM
2011 - Equipe labélisée - FRM
2009 - Senior Chaire d’Excellence - ANR
1997 - MRC (Medical Research Council) Career Development Award (UK)
1994 - EU Fellowship
1993 - EMBO Fellowship
iBV - Institut de Biologie Valrose
"Centre de Biochimie"
Université Nice Sophia Antipolis
Faculté des Sciences
06108 Nice cedex 2