Biology subjects

Perthame, E.

Publications and source records attributed to Perthame, E..

4 recordsLinked to original sources

bioRxiv2024

Notch3 is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart looping

The TGF{beta} secreted factor NODAL is a major left determinant required for the asymmetric morphogenesis of visceral organs, including the heart. Yet, when this signalling is absent, shape asymmetry, for example of the embryonic heart loop, is not fully abrogated, indicating that there are other factors regulating left-right patterning. Here, we used a tailored transcriptomic approach to screen for genes asymmetrically expressed in the field of heart progenitors. We thus identify Notch3 as a novel left-enriched gene and validate, by quantitative in situ hybridization, its transient asymmetry in the lateral plate mesoderm and node crown, overlapping with Nodal. In mutant embryos, we analysed the regulatory hierarchy and demonstrate that Nodal in the lateral plate mesoderm amplifies Notch3 asymmetric expression. The function of Notch3 was uncovered in an allelic series of mutants. In single neonate mutants, we observe that Notch3 is required with partial penetrance for the development of ventricles, in addition to its known role in coronary arteries. In compound mutants, we reveal that Notch3 acts as a genetic modifier of Nodal, able to modulate heart looping direction and the curvature of the outflow tract. Whereas Notch3 was previously associated with the CADASIL syndrome, its contribution to asymmetric organogenesis is now relevant to severe laterality defects such as the heterotaxy syndrome.

developmental biology↗

bioRxiv2023

Torsion of the heart tube by shortage of progenitor cells : identification of Greb1l as a genetic determinant of criss-cross heart in mice

Despite their burden and impact, most congenital defects remain poorly understood by lack of knowledge of the embryological mechanisms. Here, we identify Greb1l mutants as the first mouse model of criss-cross heart. Based on 3D quantifications of shape changes, we demonstrate that torsion of the atrioventricular canal occurs together with supero-inferior ventricles at E10.5, after heart looping. Mutants phenocopy specific features of partial deficiency in retinoic acid signalling, suggesting that GREB1L is a novel modulator of this signalling. Spatio-temporal gene mapping and cross-correlated transcriptomic analyses further reveal the role of Greb1l in maintaining a pool of precursor cells during heart tube elongation, by controlling ribosome biogenesis and cell differentiation. Growth arrest and malposition of the outflow tract are predictive of abnormal tube remodelling in mutants. Our work on a rare cardiac malformation opens novel perspectives on the origin of a broader spectrum of congenital defects associated with GREB1L in humans. HighlightsO_LIGreb1l inactivation is the first model of criss-cross heart C_LIO_LIGrowth arrest of the outflow tract and reduced pole distance are predictive of the torsion of the atrioventricular canal, and also account for associated defects of supero-inferior ventricles and malposition of the great vessels C_LIO_LIVentricle position needs to be maintained after heart looping C_LIO_LIGREB1L, which is associated in humans with a spectrum of congenital defects, is required to maintain precursor cells, by promoting ribosome biogenesis and restricting cell differentiation. C_LIO_LIGREB1L is a novel factor involved in retinoic acid signalling. C_LI In BriefGREB1L is associated with a spectrum of congenital defects in humans. Bernheim et al now uncover its function in maintaining a reservoir of precursor cells. Inactivation of Greb1l in the mouse impairs the elongation of the heart tube leading to criss-cross heart with supero-inferior ventricles.

developmental biology↗

bioRxiv2020

Patient-derived Glioblastoma Stem cells transfer mitochondria through Tunneling Nanotubes in Tumor Organoids

Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSLCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype. Here, we investigated whether GBM cells are capable to intercommunicate by TNTs. Two GBM stem-like cells (GSLCs) were obtained from the external and infiltrative zone of one GBM from one patient. We show, for the first time, that both GSLCs, grown in classical 2D culture and in 3D-tumor organoids, formed functional TNTs which allowed mitochondria transfer. In the organoid model, recapitulative of several tumors features, we observed the formation of a network between cells constituted of both Tumor Microtubes (TMs), previously observed in vivo, and TNTs. In addition, the two GSLCs exhibited different responses to irradiation in terms of TNT induction and mitochondria transfer, although the correlation with the disease progression and therapy-resistance needs to be further addressed. Thus, TNT-based communication is active in different GSLCs derived from the external tumoral areas associated to GBM relapse, and we propose that they participate together with TMs in tumor networking.

cancer biology↗

bioRxiv2019

The impact of rainfall on drinking water quality in Antananarivo, Madagascar

Low-income cities that are subject to high population pressure and vulnerable to climate events often have a low capacity to continuously deliver safe drinking water. Here we report the findings of a 32-year investigation of the temporal dynamics of indicators of drinking water quality in the city of Antananarivo, where we assess the long-term evolution of supplied water quality and characterize the interactions between climate conditions and the full-scale supply system. A total of 25,467 water samples were collected every week at different points in the supplied drinking water system. Samples were analyzed for total coliforms (TC), Escherichia coli (EC), intestinal Enterococci (IE), and spores of Clostridia (SSRC). Nine-hundred-eighty-one samples that were identified as positive for one or more indicators were unevenly distributed across the series. The breakpoint method identified four periods when the time series displayed changes in the level and profile of contamination (i) and the monthly pattern of contamination (ii), with more direct effects of rainfall on the quality of supplied drinking water. The modeling showed significantly different lags among indicators of bacteria occurrence after cumulative rainfall, which range from 4 to 8 weeks. Among the effects of low-income urbanization, a rapid demographic transition and urban watershed degradation are progressively affecting the quality of supplied water and resulting in the more direct effects of rainfall events.

microbiology↗