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Epigenetic and transcriptional regulation of barrelette map formation

English title Epigenetic and transcriptional regulation of barrelette map formation
Applicant Rijli Filippo
Number 175776
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 01.08.2018 - 31.07.2022
Approved amount 955'592.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Molecular Biology

Keywords (7)

Mouse hindbrain development; Epigenetics and gene regulation; Neuronal identity and pattern formation; Epigenetic regulation and chromatin; Hox transcription factors; Somatosensory topographic map; Developmental neurobiology

Lay Summary (French)

Lead
La capacité du système nerveux à intégrer l'information sensorielle et produire des comportements contrôlés repose en partie sur l'assemblage de cartes topographiques de la connectivité neuronale pendant le développement du cerveau. La dissection des principes moléculaires qui sous-tendent la formation de ces cartes cérébrales des neurones interconnectés est un objectif principal des neurosciences du développement. Cependant, les mécanismes permettant la transcription coordonnée des gènes qui sous-tendent l'établissement d'une connectivité précise in vivo sont encore peu connus.
Lay summary

Le principal objectif novateur de ce projet est de découvrir les signatures épigénétiques de la chromatine qui sous-tendent la transcription coordonnée des gènes dans les neurones sensoriels lors du développement du circuit trigéminal. Dans ce circuit, la disposition spatiale des neurones et de leurs fibres afférentes réitère la distribution physique des moustaches sensorielles sur le visage de la souris, générant une représentation somatotopique (soma : corps) fidèle de la face dans le cerveau.

L'identification des mécanismes moléculaires qui établissent une connectivité précise et établissent une cartographie cérébrale de la sensation somatique à partir du corps peut fournir le travail de base pour trouver des traitements potentiels pour le re-mappage du cerveau à la suite d'une lésion et une meilleure compréhension de l'étiologie de certains troubles neuro-développementaux.

Direct link to Lay Summary Last update: 14.06.2018

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Associated projects

Number Title Start Funding scheme
173868 Sinergia Project: A Tissue, Cell and Molecular Approach to Understanding and Treating Microtia 01.01.2018 Sinergia

Abstract

The ability of the nervous system to integrate sensory information and produce well-controlled behaviors relies in part on the assembly of topographic maps of neuronal connectivity during brain development. The dissection of the molecular and cellular principles underlying the formation of these brain maps of interconnected neurons is a main goal in developmental neuroscience. The general aim of this research plan is to investigate the epigenetic and transcriptional regulation of topographic circuit formation.The establishment of topographic connectivity maps, serially wired through peripheral and central sub-cortical and cortical stations, relies on intrinsic and extrinsic molecular processes that result in spatial and temporal control of gene transcription in subsets of connecting neurons during prenatal and postnatal development. During prenatal development, neurons from distinct regions of the brain are targeted by axonal projections in a stereotypic manner. During postnatal development, the combination of genetic regulation and environmental input experienced by the individual refines these circuits in an activity-dependent manner and eventually results in the precise maps of neuronal wiring of the adult brain. However, the mechanisms allowing coordinated gene transcription in vivo underlying the establishment of point-to-point connectivity are still unknown.This project aims at bridging neuronal circuit development and epigenetics and focuses on the assembly of a highly topographic circuit, the mouse whisker-to-barrel somatosensory pathway. In this circuit, the spatial arrangement of neurons and their afferent fibers reiterates the physical distribution of sensory whiskers on the mouse face, generating a somatotopic representation in the brain. This ability of the brain to faithfully map the body surface is exemplified in the concept of the homunculus of Penfield. The main innovative aim of this proposal is to discover chromatin epigenetic signatures underlying coordinated gene transcription in neurons during the establishment of point-to-point connectivity. We will specifically investigate the epigenetic regulation of chromatin states during formation of maps of neuronal modules, termed barrelettes, relaying whisker-specific somatosensory information in the mouse brainstem. We recently found that the homeobox transcription factor gene Hoxa2 is necessary and sufficient to drive the assembly of the barrelette circuitry. By ad hoc genetic tools, we will isolate brainstem barrelette sensory neurons at different stages and map HOX transcription factor occupancy (ChIP-Seq), as well as histone modifications (ChIP-Seq) and chromatin accessibility (ATAC-Seq) profiles to identify the neuronal enhancers involved in transcriptional regulation of barrelette neuron identity and connectivity. Furthermore, we will identify activity-dependent chromatin accessibility and enhancer signatures by profiling genetically silenced barrelette neurons and comparing them with control barrelette neurons. These analyses will be complemented by transcriptome (RNA-Seq) and selected enhancer-promoter 3D-interaction studies (4C-Seq).These studies will provide novel insights into the epigenetic and transcriptional regulation of topographic fate and point-to-point connectivity programs in the developing central nervous system. Moreover, the identification of the molecular mechanisms that establish precise connectivity and build accurate mapping of somatic sensation from the body may provide the ground work for finding potential treatments for brain remapping following injury and a better understanding of the etiology of certain neurodevelopmental disorders.
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