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Comparative analysis of stem cells, brain anatomy and homeostasis (CASBAH)

Team leader : Jean-Stéphane Joly

We use fish models, whose brains have the peculiarity to grow continuously during whole animal life. We identified, in the mesencephale, a unique layer of slow-amplifying progenitors (SAP) accessible for long term in vivo imaging. They are adjacent to the optic tectum, which has transitory fast amplifying progenitors (FAP) at its margin. As in the retina, the presence of these SAP and FAP in separate domains speeds their multilevel characterization, and the functional characterization of SAP markers. SAPs share many features with neural stem cells (NSCs).

Therefore our comparative study of NSCs should document their diversity and identify essential/core gene-regulatory mechanisms.

We tackle three main fundamental questions in the field of NSC biology :
- what are the specific features and genes of midbrain neuroepithelial stem cells (NeSCs) ? In particular, we focus our interests on ribosome biogenesis genes.
- How NeSC homeostasy is regulated in healthy or pathological conditions : under modified nutritional states and during regeneration ?
- How transcription of key genes is regulated in NeSCs ?

Scientific background

Most progenitors of the mammalian forebrain have been shown to be of radial/astrocytic glial nature. However, other types of slow-cycling progenitors have recently been described, which retain neuroepithelial features or display ependymal characteristics. They are crucial for regeneration In aquatic vertebrates and have recently been shown to have key roles in reparation events in the mouse spinal cord.
In the adult zebrafish brain, sixteen cell proliferation zones have been described (Grandel et al., 2006, Chapouton, 2007).
This high number of proliferation/stem cell zones is associated with the capacity of the fish brain to grow continuously at adulthood.
We focus on a midbrain layer containing neuroepithelial progenitors (NeSC). We refer to it as the “Peripheral Midbrain Layer” (PML).

Scientific projects

An ongoing work of the group consists in performing a description of the PML cells and progenitors of the optic tectum (OT) by 3D/4D imaging (collaboration with N. Peyrieras, Recher et al. 2013) and at the ultrastructural level at embryonic, juvenile and adult stages (Jean-Michel Hermel).
Using fluorescent lines, we describe the cell diversity of the tectal progenitors (Aurélie Heuzé). To perform these studies a screen of twelve ultraconserved mouse elements was performed in zebrafish (Aurélie Heuzé). Also we currently use several enhancers provided by F. Del Bene and K. Kawakami labs.
Our comparative approaches focus on the comparison of visual systems in Drosophila and fish (Jean-Stéphane Joly) and on the evolutionary history of the cellular conveyor belt growth mode (Franck Bourrat).


- 1- What are the important genetic components for NeSC function ? (Françoise Jamen, Franck Bourrat, Emilie Mugniery, Alessandro Brombin)

Key genes for the cell cycle exit in PML and tectum progenitors have been identified following a systematic study of the expression patterns of so-called anti-oncogenes (Franck Bourrat). A project is focused on the function of the BTG-1 gene in cell-cycle exit (Franck Bourrat). To point to stem-cell-specific quiescence mechanisms, we wish to characterize the functions of other genes with reinforced expressions in the stem cells.

To further document the biology of PML cells, we have selected several families of genes essential for ribosome biogenesis (Françoise Jamen, Alessandro Brombin, and Emilie Mugniery). We wish to understand the origin of the strikingly convergent phenotypes of the mutants for the PML genes.


- 2- How are NeSCs recruited in abnormal situations ? (Tibiabin Benitez-Santana and Aurélie Heuzé, In collaboration with Françoise Médale and Geneviève Corraze)

Regulation of NeSC by the nutritional context (Tibiabin Benitez-Santana and Matthieu Simion).

Changes in the nutritional status of the organism can indirectly affect stem cells by modulating the proliferation activity. We wish to study how zebrafish stem cells are regulated by changes in nutritional status. We wish to determine which signaling pathways are involved in homeostasy maintenance. This study paves the route for future experiments aiming at the analysis the relationship between diet composition and NSC homeostasis.

Regulation of NeC Function in a pathological context (Aurélie Heuzé)

Fish models have extraordinary capacities for self-repair and more specifically for neuronal regeneration. By expressing a toxic nitroreductase protein at different time points, we ablate subpopulations of differentiated neurons present in the central part of the juvenile and adult zebrafish tectum to study the behavior of regeneration foci.


- 3- How transcription regulation is achieved in NeSC ? (Jean-Stéphane Joly and Matthieu Simion)

Characterisation of midbrain NeSC regulatory elements (Matthieu Simion)
We focus on a few PML gene loci and perform, in medaka and zebrafish, a molecular dissection of the regulatory sequences of couples of PML genes arranged in tandem. Most PML genes code for protein families which are usually expressed ubiquitously. In NeSC, PML genes seem to achieve a boosted and restricted expression through specific flanking regions, while proximal elements participate in a strong basal activation.

In silico characterization of midbrain and midbrain stem cell logics (Jean-Stéphane Joly and Matthieu Simion)

To understand the regulatory logics in midbrain and more specifically in midbrain stem cells, we perform several in silico searches for over-represented motives, or for key motives identified with learning machines. We use several lists of elements collected in mice and zebrafish in the Enhancer Browser, Eurexpress or Zfin.

Characterization of midbrain NeSC chromatin marks (in collaboration with Pierre-Olivier Angrand and Laure Bally-Cuif). This project will characterize active chromatine regions in midbrain NeSC.

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