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
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
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.
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).
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.
·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