WNT/T-Cell Factor (TCF) Signaling in the Biology of Cerebellar Granular Neuron Progenitors

Our team is interested in understanding the molecular and cellular mechanisms that control development in vertebrate embryos, and the deregulations of these processes associated with the emergence of human diseases. We focus our research on the role of Wnt/T-cell Factors (TCF) signaling in the emergence of neural stem cell niches and more specifically the rhombic lip of the cerebellum.

We use the Xenopus and mouse as model systems, which are complementarily and adapted to in vivo and in vitro analyses. We use large-scale approaches in cellular and molecular biology, biochemistry, and experimental biology. Our goal is to highlight common events that occur during early development and in human pathologies. Identification and functional analysis of key factors that modulate the activation and/or repression of Wnt signaling in vertebrate embryos. Specifically, we are interested in TCF regulators that play a prominent role in the irreversible exit from a multipotent state and in BarH-like homeodomain transcription factors (BARHL1 and BARHL2), functioning as irreversible inhibitor of Wnt/TCF dependent transcription.

To Know More

During embryonic development, stem/progenitor cells gradually lose their multipotency. The commitment/differentiation process is unidirectional, and is prevented from reversing by molecular locks. It is essential to understand the transcriptional and epigenetic events that occur behind these locks in stem/progenitor cells; when corrupted, they promote tumor emergence and spreading.

Wnt signaling is involved in many biological processes, including embryonic axis formation, cell proliferation, differentiation and migration, and the establishment of cell polarity. Its deregulation is responsible for various human diseases such as cancer. The cerebellar rhombic lip (cRhL) generates the largest population of neurons in the brain: granule neurons. A subpopulation of granular neuron progenitors, the early GNPs (eGNPs), is at the origin of medulloblastoma (MB), the most common malignant brain tumor in children. The project of the team concerns the identification and functional analysis of the Wnt/TCF signaling pathways and its interaction with the Notch and Sonic HedgeHog pathways in the emergence of granular neurons and the biology of eGNPs.

Importants Results

The BarH-like homeodomain transcription factor (BARHL2) is highly conserved during evolution. We have shown that it acts as a transcriptional repressor in the Wnt signaling pathway via its interaction with TCF7l1, Groucho, and histone deacetylase 1 (HDAC1), resulting in the formation of regionalized and inherited repressive chromatin structures (Development 2019).

Projects

We are studying the role of BARHL1 and BARHL2 transcription factors that are direct targets genes of ATOH1 factor. We are focusing on BARHLs roles in the biology of cerebellar granular neuron stem/progenitoring cells, at the origin of a malignant brain tumor in children, medulloblastoma.

Collaborations

·R. Sherrard Repairing Neuronal Networks

·Transcriptomic Analysis - Institut Curie - U1021, Orsay, France.

Single Cell Analysis - Institut du Cerveau et de la Moelle (ICM) - Paris, France