Biology subjects

Causeret, F.

Publications and source records attributed to Causeret, F..

6 recordsLinked to original sources

bioRxiv2024

Differential contribution of P73+ Cajal-Retzius cells and Reelin to cortical morphogenesis

Cajal-Retzius cells (CRs) are a peculiar neuronal type within the developing mammalian cerebral cortex. One of their best documented feature is the robust secretion of Reln, a glycoprotein essential for the establishment of cortical layers through the control of radial migration of glutamatergic neurons. We previously identified Gmnc as a critical fate determinant for P73+ CRs subtypes from the hem, septum and thalamic eminence. In Gmnc-/- mutants, P73+ CRs are initially produced, cover the telencephalic vesicle but undergo massive apoptosis resulting in their complete depletion at mid-corticogenesis. Here we investigated the consequence of such a CRs depletion on dorsal cortex lamination and hippocampal morphogenesis. We found preplate splitting occurs normally in Gmnc-/- mutants but is followed by defective radial migration arrest in the dorsal cortex, altered cellular organization in the lateral cortex, aberrant hippocampal progenitor proliferation resulting in abnormal CA1 folding and lack of vasculature development in the hippocampal fissure. We then performed conditional Reln deletion in P73+ CRs to evaluate its relative contribution and found that only radial migration defects were recapitulated. We concluded that at mid-corticogenesis, CRs-derived Reln is required for radial migration arrest and additionally identified Reln-independent functions for CRs in the control of hippocampal progenitor proliferation and vessel remodelling.

neuroscience↗

bioRxiv2023

Bidirectional interaction between Protocadherin 8 and transcription factor Dbx1 regulates cerebral cortex development

Brain development requires correct tissue patterning and production of appropriate cell types. Transcription factors (TFs) play essential roles in these processes, regulating the expression of target genes responsible for neuronal subtypes specific features. Cell adhesion molecules are key components of developmental processes that control cell sorting, migration, neurite outgrowth/guidance and synaptogenesis. To date, the link between TFs and cell adhesion molecules is considered to be unidirectional. Here, we demonstrate that ectopic expression of Dbx1 leads to spatio-temporally restricted increased expression of Pcdh8 and cell aggregation, together with changes in neuronal identity. Surprisingly, Pcdh8 overexpression also induces Dbx1 expression as well as a complete reorganisation of apico-basal polarity and dorso-ventral patterning via Notch signalling. Altogether, our work therefore points to cell adhesion molecules as unexpected, yet important, players in the regulation of cell identity and, in particular, Pcdh8 through its bidirectional interaction with the Dbx1 transcription factor.

neuroscience↗

bioRxiv2022

Diversity within olfactory sensory derivatives revealed by the contribution of Dbx1 lineages

In vertebrates, the embryonic olfactory epithelium contains progenitors that will give rise to distinct classes of neurons, including olfactory sensory neurons (OSN, involved in odor detection), vomeronasal sensory neurons (VSN, responsible for pheromone sensing) and GnRH neurons that control the hypothalamic-pituitary-gonadal axis. Currently, these three neuronal lineages are usually believed to emerge from uniform pools of progenitors. Here we found that the homeodomain transcription factor Dbx1 is expressed by neurogenic progenitors in the developing and adult mouse olfactory epithelium. We demonstrate that Dbx1 itself is dispensable for neuronal fate specification and global organization of the olfactory sensory system. Using lineage tracing we characterize the contribution of Dbx1 lineages to OSN, VSN and GnRH neuron populations and reveal an unexpected degree of diversity. Furthermore, we demonstrate that Dbx1-expressing progenitors remain neurogenic in the absence of the proneural gene Ascl1. Our work therefore points to the existence of distinct neurogenic programs in Dbx1-derived and other olfactory lineages.

developmental biology↗

bioRxiv2021

Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.

neuroscience↗

bioRxiv2020

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

In the developing cerebral cortex, how progenitors that seemingly display limited diversity end up in producing a vast array of neurons remains a puzzling question. The prevailing model that recently emerged suggests that temporal maturation of these progenitors is a key driver in the diversification of the neuronal output. However, temporal constrains are unlikely to account for all diversity across cortical regions, especially in the ventral and lateral domains where neuronal types significantly differ from their dorsal neocortical counterparts born at the same time. In this study, we implemented single-cell RNAseq to sample the diversity of progenitors and neurons along the dorso-ventral axis of the early developing pallium. We first identified neuronal types, mapped them on the tissue and performed genetic tracing to determine their origin. By characterising progenitor diversity, we disentangled the gene expression modules underlying temporal vs spatial regulations of neuronal specification. Finally, we reconstructed the developmental trajectories followed by ventral and dorsal pallial neurons to identify gene waves specific of each lineage. Our data suggest a model by which discrete neuronal fate acquisition from a continuous gradient of progenitors results from the superimposition of spatial information and temporal maturation.

developmental biology↗

bioRxiv2020

The PAXFOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition

The chromosome translocations generating PAX3FOXO1 and PAX7FOXO1 chimeric proteins are the primary hallmarks of the paediatric cancer, Alveolar Rhabdomyosarcoma (ARMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAXFOXO1s. Our data demonstrate that PAXFOXO1s, but not wild-type PAX3 and PAX7, trigger the trans-differentiation of neural cells into ARMS-like cells with myogenic characteristics. In parallel expression of PAXFOXO1s remodels the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, gain for PAXFOXO1s, as for wild-type PAX3/7, reduces the levels of CDK-CYCLIN activity and arrests cells in G1. Introduction of CYCLIN D1 or MYCN overcomes PAXFOXO1s mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism underpinning the apparent limited oncogenicity of PAXFOXO1 fusion transcription factors and support a neural origin for ARMS.

cancer biology↗