Comparative studies of CNS development

Evolutionary mechanisms controlling telencephalon complexity

Anterior Neural Border (ANB) signalling and induction of telencephalic fate

Repression of Wnt signalling by antagonists secreted from the ANB is a major requirement for the induction of prosencephalic fate, comprising telencephalon and eye field. However, the differential regionalisation of medial (eye field) vs. marginal (Telencephalon) fates is Wnt independent. They showed that BMP signalling is partitioning the prosencephalic field into telencephalon and eye (Bielen & Houart, 2013). We are now investigating the spatio-temporal regulation of ANB signalling in the anterior neural plate as evolutionary mechanism controlling telencephalic size in vertebrates.

Unveiling evolutionary mechanisms using scRNAseq and telencephalic organoids

To understand the dynamics of gene regulation leading to forebrain diversity across vertebrates, the Houart lab is following forebrain cell fate specification in zebrafish, mouse and human, achieving cell date clustering across time in these three species from fresh tissues and modelling evolutionary variation in vitro using 3D culture models.

Telencephalon organisation & cellular excitatory/inhibitory balance

Cellular Input Integration from Forebrain Signalling Centres

In the last years, research as shed light on the mechanism by which secreted molecules, released by signalling centres, establish cell fate specification in complex tissues. The mechanism by which a cell integrates the information received from a set of signals is yet to be elucidated. They use the telencephalon to tackle this issue, assessing how progenitors define their identity in response to two signalling centres: a ventral Hh-secreted and a dorsal Wnt-secreted centres. They identified the transcription factor Foxg1 as an integrator of these two signals (Danesin et al., 2009) and are now identifying the partners of Foxg1 in this process.

Temporal Progression of FOXG1 Syndrome and Avenues for Therapies

Making use of their knowledge of FOXG1 biology, the team is using zebrafish heterozygous mutants to understand the cellular and molecular spatio-temporal events leading to FOXG1 syndrome in human. Findings made in zebrafish is validated in human using iPSC-derived neuronal culture from patients.

Non-nuclear mRNA/splicing factor interactions in axonal maturation

Axonal and nuclear pools of splicing factors essential for neuronal maturation

The Houart lab have shown that nuclear and cytoplasmic SFPQ is essential for motor neuron development (Thomas-Jinu, 2017). The nuclear pool prevents splicing of cryptic las exons (CLEs, Gordon et al., 2020). Axonal pools of splicing factors (SFPQ) and spliceosome proteins (snRNP70) are essential for neuronal maturation and shape the local transcriptome (Thomas-Jinu, 2017; Nikolaou et al., 2021; Taylor et al., 2021). They are currently addressing the molecular mechanisms carrying on their cytoplasmic functions.

Modulation of local decision-making by axonal intron retaining transcripts

In wildtype neurons, a series of very specific intron retaining transcripts are transported in the axons and dendrites in a regulated fashion during neuronal maturation. The team is exploring their role, the spatio-temporal dynamics of these mRNAs and their highly-controlled local translation.

Developmental signalling in cell-cell interaction

Non-canonical Dkk1 function in control of cell motility

The lab discovered that the Wnt antagonist Dkk1 is controlling cell adhesion and polarity independently of the Wnt/βcatenin pathway (Caneparo et al., 2007; Johansson et al., 2019). They are currently exploring the nature of the molecular interaction leading to Dkk1 modulation of adhesion and motility. Identifying Dkk1 direct interactor(s) in this process will also have impact in understanding the role of Dkk1 in synaptic stabilisation, neurodegeneration and cancer metastatic processes.