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Transcriptional and epigenetic regulation of precerebellar neuron migration and connectivity

English title Transcriptional and epigenetic regulation of precerebellar neuron migration and connectivity
Applicant Rijli Filippo
Number 149573
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Embryology, Developmental Biology
Start/End 01.01.2014 - 30.09.2017
Approved amount 760'962.00
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All Disciplines (3)

Discipline
Embryology, Developmental Biology
Molecular Biology
Neurophysiology and Brain Research

Keywords (15)

hindbrain development; transgenic and knockout mice; precerebellar system; transcriptional regulation; transcription factors; topographic axonal connectivity; body map; somatosensory pathways; motor pathways; epigenetic regulators; retinoic acid; Hox genes; corticofugal connectivity; cerebellar map; cortical map

Lay Summary (French)

Lead
La capacité du système nerveux à intégrer l'information sensorielle et produire des comportements moteurs bien contrôlées repose sur l'assemblage précis des réseaux neuronaux au cours du développement du cerveau. Cependant, les mécanismes moléculaires qui sous-tendent au développement de cette connectivité complexe sont peu connus. L'objectif de ce projet est d’étudier les mécanismes de régulation transcriptionnelle lors de la formation du circuit pré-cérébelleux dans le tronc cérébrale murin.
Lay summary

L'objectif général de ce projet de recherche est d’étudier les mécanismes de régulation transcriptionnelle lors de la formation des circuits neuronaux. Pour ce faire, nous allons étudier le développement des noyaux pre-cérébelleux pontiques dans le tronc cérébrale de la souris. Ces noyaux, qui sont nécessaires pour une activité motrice coordonnée, reçoivent les afférences du cortex sensoriel et moteur et les relayaient au cervelet. Les neurones des noyaux pontiques sont générés dans une partie du tronc cérébrale éloignée du cervelet, de sorte qu'ils doivent entreprendre une migration de longue distance pour atteindre leur destination finale. Au cours du développement prénatal, sous-ensembles distincts de neurones pontiques suivent une route migratoire très précise en fonction de leur origine rostrocaudale et de leurs programmes intrinsèques d’expression génique, qui leur permettent de répondre de façon appropriée aux signaux environnementaux et d'être conduits à leur destination finale. Chacune de ces sous-populations distinctes de neurones est dotée d'un ‘code’ d’expression spécifique de facteurs de transcription. L'hypothèse abordée dans ce projet, c'est que ce code transcriptionnel puisse conférer la spécificité du choix du partenaire synaptique aux neurones pre-cérébelleux pontiques au cours de la formation du circuit cortico-ponto-cérébellaire. Le projet fera appel à un large éventail d'outils génétiques chez la souris et d'une combinaison d' approches moléculaires, cellulaires et anatomiques.
Ce projet de recherche fondamentale pourra faire avancer notre compréhension des mécanismes moléculaires contrôlant le développement de circuits complexes dans le cerveau des mammifères. Les connaissances issues de ce projet pourront aussi apporter une contribution utile à la compréhension des maladies du système nerveux liés à des molécules impliquées dans le développement des circuits neuronaux, comme l'autisme et d'autres maladies neurologiques.

 

 

Direct link to Lay Summary Last update: 25.10.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A mutant with bilateral whisker to barrel inputs unveils somatosensory mapping rules in the cerebral cortex.
Renier N Dominici C Erzurumlu RS Kratochwil CF Rijli FM Gaspar P Chédotal A. (2017), A mutant with bilateral whisker to barrel inputs unveils somatosensory mapping rules in the cerebral cortex., in eLife, 23494.
Gene bivalency at Polycomb domains regulates cranial neural crest positional identity.
Minoux M Holwerda S Vitobello A Kitazawa T Kohler H Stadler M Rijli FM (2017), Gene bivalency at Polycomb domains regulates cranial neural crest positional identity., in Science (New York, N.Y.), 2913.
Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem.
Karmakar K Narita Y Fadok J Loche A Fadok J Genoud C Ducret S Di MeglioT Thierry R Bacelo J, Luthi A Rijli FM (2017), Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem., in Cell reports, 185.
Nuclear Pore Protein Meets Transcription Factor in Neural Fate.
Kitazawa T Rijli FM (2017), Nuclear Pore Protein Meets Transcription Factor in Neural Fate., in Neuron, 259.
Prenatal thalamic waves regulate cortical area size prior to sensory processing.
Moreno-Juan V Filipchuk A Antón-Bolaños N Mezzera C Gezelius H Andrés B Rodriguez Malmierca L, Susín R Schaad O Rutlin M Nelson S Ducret S Valdeolmillos M Rijli FM López-Bendito G (2017), Prenatal thalamic waves regulate cortical area size prior to sensory processing., in Nature communications, 14172.
The formation of the light-sensing compartment of cone photoreceptors coincides with a transcriptional switch.
Daum JM Keles Ö Holwerda SJ Kohler H Rijli FM Stadler M Roska B (2017), The formation of the light-sensing compartment of cone photoreceptors coincides with a transcriptional switch., in Elife, 31437.
The Long Journey of Pontine Nuclei Neurons: From Rhombic Lip to Cortico-Ponto-Cerebellar Circuitry.
Kratochwil CF Maheshwari U Rijli FM (2017), The Long Journey of Pontine Nuclei Neurons: From Rhombic Lip to Cortico-Ponto-Cerebellar Circuitry., in Frontiers in neural circuits, 33.
Facial whisker pattern is not sufficient to instruct a whisker-related topographic map in the mouse somatosensory brainstem.
Laumonnerie C* Bechara A* Vilain N Kurihara Y Kurihara H Rijli FM (2015), Facial whisker pattern is not sufficient to instruct a whisker-related topographic map in the mouse somatosensory brainstem., in Development (Cambridge, England), 3704.
Hoxa2 Selects Barrelette Neuron Identity and Connectivity in the Mouse Somatosensory Brainstem.
Bechara A Laumonnerie C Vilain N Kratochwil C Cankovic V Maiorano N, Kirschmann M Ducret S Rijli FM (2015), Hoxa2 Selects Barrelette Neuron Identity and Connectivity in the Mouse Somatosensory Brainstem., in Cell reports, 783.
Parallel pathways from motor and somatosensory cortex for controlling whisker movements in mice.
Sreenivasan V Karmakar K Rijli FM and Petersen CCH (2015), Parallel pathways from motor and somatosensory cortex for controlling whisker movements in mice., in The European journal of neuroscience, 354.
Perinatal induction of Cre recombination with tamoxifen.
Lizen B Claus M Jeannotte L Rijli FM Gofflot F (2015), Perinatal induction of Cre recombination with tamoxifen., in Transgenic research, 1065.
The Cre/Lox system to assess the development of the mouse brain.
Kratochwil CF Rijli FM (2014), The Cre/Lox system to assess the development of the mouse brain., in Methods in molecular biology (Clifton, N.J.), 295.

Associated projects

Number Title Start Funding scheme
127440 Transcriptional mechanisms of circuit formation and synapse specification 01.01.2010 Sinergia

Abstract

The ability of the nervous system to integrate complex sensory information and produce well-controlled behaviors relies on the precise assembly of neuronal networks during brain development. The general goal of this research plan is to examine key aspects of transcriptional regulation during circuit assembly. To accomplish this goal, we will focus on the epigenetic and transcriptional control of directional migration and connectivity patterns of selected subsets of precerebellar neurons. In particular, we will study the development of the pontine nuclei, which receive cortical input and provide main mossy fiber output to cerebellum, as a first step to unravel the complex logics of cortico-ponto-cerebellar connectivity. The key hypothesis addressed in this proposal is that rostrocaudal origin and Hox gene transcriptional programs in precerebellar neuron subsets allow to allocate neuronal subsets at specific positions within the mature nuclei, and, in turn, provide neurons with specific transcriptional codes for the specificity of input-output synaptic partner choice (i.e. selective attraction/repulsion of afferent input from distinct cortical areas and output to specific lobes of the cerebellum). The project will make use of a wide range of ad hoc genetic tools in the mouse and will utilise a combination of molecular, cellular and anatomical approaches. We will mechanistically address the impact of environmental signalling, namely retinoic acid secreted from the meninges overlying pontine neurons, on the epigenetic and transcriptional regulation at the promoter of a key transcription factor, Hoxa5, as a novel mechanism to generate a temporally and spatially restricted neuronal subpopulation of precerebellar neurons. Moreover, we will examine the relationship between Hox-expressing pontine neuron subsets, their final nuclear position, and the topography of their afferent/efferent (i.e. cortico-ponto) connectivity pathways. A specific focus will be on the role of Hox PG5 genes in providing unique cortical afferent and cerebellar efferent projection patterns to precerebellar neuron subsets. In the long-term, such studies are expected to further our understanding of the molecular mechanims involved in transforming cortical into cerebellar sensorymotor maps.
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