Transcription factors and cell fate

Vanessa RIBES

Our research projects aim to better understand the plasticity and stability of cellular phenotypes by analysing the generation of neuronal diversity within the embryonic spinal cord and the transformation that leads to rhabdomyosarcomas, paediatric cancers. In particular, we focus on PAX transcription factors whose modular activity is able to generate an incredible diversity of cell states.

Keywords: cell differentiation, transcription factors, embryonic spinal cord, Rhabdomyosarcoma, Spina Bifida, PAX, organoids, pluripotent stem cells

+33 (0)157278193 vanessa.ribes(at)ijm.fr @VanessaRibes https://ribeslab.wordpress.com/

Research

Our laboratory studies the establishment of cell fates through two major projects. First, we are exploring how neuronal diversity emerges in the embryonic spinal cord. Secondly, we are investigating the means by which gene networks linked to PAX factor activity control tissue remodelling. Both projects have implications for our understanding of two childhood diseases, rhabdomyosarcoma and spina bifida. These projects are mainly approached using spinal cord organoids that we generate from pluripotent stem cells. These are models that recapitulate the physiology of tissues, including human ones, and are highly malleable, allowing in particular the implementation of genetic engineering and pharmacological approaches.

PATTERNING NEURAL DIVERSITY:

The stereotypical organisation of neuronal diversity in the spinal cord is astonishing and is essential for the function of motor and sensory circuits. Hundreds of neuronal subtypes are generated at a specific location along the anteroposterior and dorsoventral axes of the neural tube. The correspondence between cell coordinates and cell fate is ensured by the combined action of secreted signalling molecules, such as Shh or BMP morphogens, and intrinsic cell fate determinants, including PAX transcription factors. Together, they are responsible for the generation of banded patterns of gene expression, organised along the orthogonal axes of the developing neural tube.

We are interested in how these gene expression bands are generated and how they are translated into specific cellular behaviours and states. In particular, we are paying close attention to the modulation of the transcriptional activity of PAX factors. They are able to both activate and repress gene expression and this bivalence is regulated in space and time. We are investigating how pleiotropism in PAX activity is generated and read out at the genome level and which structural protein partners and domains support this pleiotropism.

TISSUE REMODELLING:

The dynamics of cell shape within epithelia underlie the morphogenesis of many organs. The same is true for the formation of the spinal cord, which is accompanied by extensive remodelling of its pseudostratified epithelium. These include the bending and fusion of the caudal neural plate into a tube, the epithelial-mesenchymal transition (EMT) of the dorsal neural crest cells (NCC) and the delamination of early born neurons.

All of these events are under the control of PAX3 and PAX7 protein activity and disruptions in PAX activity in humans can lead to pathological conditions. These include spina bifida, a congenital disease resulting from a neural tube closure defect, or the metastatic behaviour of rhabdomyosarcoma. Hence our interest in understanding the means by which PAX activity and associated gene networks are able to generate diversity in epithelial cell shape and behaviour.

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Members

Group Leader:

Vanessa RIBES

Email : vanessa.ribes (at) ijm.fr

Phone : +33 (0)157278193

Members:

Pascale	GILARDI HEBENSTREIT	Researcher
Camil	MIRDASS	PhD student
Robin	RONDON	PhD student
Kenza	CHERIET	PhD student
Claire	DUGAST	Associate professor
Lucas	DENIS
Théaud	HEZEZ	Master 2

Selected Publications

Since 2015 :

Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification. Mouilleau V, Vaslin C, Robert R, Gribaudo S, Nicolas N, Jarrige M, Terray A, Lesueur L, Mathis MW, Croft G, Daynac M, Rouiller-Fabre V, Wichterle H, Ribes V, Martinat C, Nedelec S. Development. 2021 Mar 29;148(6):dev194514. doi: 10.1242/dev.194514.

The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition. Gonzalez Curto G, Der Vartanian A, Frarma YE, Manceau L, Baldi L, Prisco S, Elarouci N, Causeret F, Korenkov D, Rigolet M, Aurade F, De Reynies A, Contremoulins V, Relaix F, Faklaris O, Briscoe J, Gilardi-Hebenstreit P, Ribes V. PLoS Genet. 2020 Nov 11;16(11):e1009164. doi: 10.1371/journal.pgen.1009164.

Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation. Darrigrand JF, Valente M, Comai G, Martinez P, Petit M, Nishinakamura R, Osorio DS, Renault G, Marchiol C, Ribes V, Cadot B. Elife. 2020 Feb 27;9:e50325. doi: 10.7554/eLife.50325.

In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Yvernogeau L, Gautier R, Petit L, Khoury H, Relaix F, Ribes V, Sang H, Charbord P, Souyri M, Robin C, Jaffredo T. Nat Cell Biol. 2019 Nov;21(11):1334-1345. doi: 10.1038/s41556-019-0410-6.

BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids. Duval N, Vaslin C, Barata TC, Frarma Y, Contremoulins V, Baudin X, Nedelec S, Ribes VC. Development. 2019 Jul 25;146(14):dev175430. doi: 10.1242/dev.175430.

The HMG box transcription factors Sox1a and Sox1b specify a new class of glycinergic interneuron in the spinal cord of zebrafish embryos. Gerber V, Yang L, Takamiya M, Ribes V, Gourain V, Peravali R, Stegmaier J, Mikut R, Reischl M, Ferg M, Rastegar S, Strähle U. Development. 2019 Feb 20;146(4):dev172510. doi: 10.1242/dev.172510.

Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons. Gard C, Gonzalez Curto G, Frarma YE, Chollet E, Duval N, Auzié V, Auradé F, Vigier L, Relaix F, Pierani A, Causeret F, Ribes V. Dev Biol. 2017 Dec 1;432(1):24-33. doi: 10.1016/j.ydbio.2017.06.014.

Structures and properties of PAX linked regulatory networks architecting and pacing the emergence of neuronal diversity. Curto GG, Gard C, Ribes V. Semin Cell Dev Biol. 2015 Aug;44:75-86. doi: 10.1016/j.semcdb.2015.09.010.

All the publications since 2017

Publications

Mirdass, C., Catala, M., Bocel, M., Nedelec, S., & Ribes, V. (2023). Stem cell-derived models of spinal neurulation. Emerging Topics in Life Sciences, 7(4), 423–437. https://doi.org/10.1042/ETLS20230087

Moniot-Perron, L., Moindrot, B., Manceau, L., Edouard, J., Jaszczyszyn, Y., Gilardi-Hebenstreit, P., Hernandez, C., Bloyer, S., & Noordermeer, D. (2023). The Drosophila Fab-7 boundary modulates Abd-B gene activity by guiding an inversion of collinear chromatin organization and alternate promoter use. Cell Reports, 42(1), 111967. https://doi.org/10.1016/j.celrep.2022.111967

Manceau, L., Richard Albert, J., Lollini, P.-L., Greenberg, M. V. C., Gilardi-Hebenstreit, P., & Ribes, V. (2022). Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs. PLoS Genetics, 18(5), e1009782. https://doi.org/10.1371/journal.pgen.1009782

Mouilleau, V., Vaslin, C., Robert, R., Gribaudo, S., Nicolas, N., Jarrige, M., Terray, A., Lesueur, L., Mathis, M. W., Croft, G., Daynac, M., Rouiller-Fabre, V., Wichterle, H., Ribes, V., Martinat, C., & Nedelec, S. (2021). Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification. Development (Cambridge, England), 148(6), dev194514. https://doi.org/10.1242/dev.194514

Gonzalez Curto, G., Der Vartanian, A., Frarma, Y. E.-M., Manceau, L., Baldi, L., Prisco, S., Elarouci, N., Causeret, F., Korenkov, D., Rigolet, M., Aurade, F., De Reynies, A., Contremoulins, V., Relaix, F., Faklaris, O., Briscoe, J., Gilardi-Hebenstreit, P., & Ribes, V. (2020). The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition. PLoS Genetics, 16(11), e1009164. https://doi.org/10.1371/journal.pgen.1009164

Clément, Y., Torbey, P., Gilardi-Hebenstreit, P., & Crollius, H. R. (2020). Enhancer–gene maps in the human and zebrafish genomes using evolutionary linkage conservation. Nucleic Acids Research, 48(5), 2357–2371. https://doi.org/10.1093/nar/gkz1199

Darrigrand, J.-F., Valente, M., Comai, G., Martinez, P., Petit, M., Nishinakamura, R., Osorio, D. S., Renault, G., Marchiol, C., Ribes, V., & Cadot, B. (2020). Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation. ELife, 9, e50325. https://doi.org/10.7554/eLife.50325

Yvernogeau, L., Gautier, R., Petit, L., Khoury, H., Relaix, F., Ribes, V., Sang, H., Charbord, P., Souyri, M., Robin, C., & Jaffredo, T. (2019). In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Nature Cell Biology, 21(11), 1334–1345. https://doi.org/10.1038/s41556-019-0410-6

Duval, N., Vaslin, C., Barata, T. C., Frarma, Y., Contremoulins, V., Baudin, X., Nedelec, S., & Ribes, V. C. (2019). BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids. Development (Cambridge, England), 146(14), dev175430. https://doi.org/10.1242/dev.175430

Gerber, V., Yang, L., Takamiya, M., Ribes, V., Gourain, V., Peravali, R., Stegmaier, J., Mikut, R., Reischl, M., Ferg, M., Rastegar, S., & Strähle, U. (2019). The HMG box transcription factors Sox1a and Sox1b specify a new class of glycinergic interneuron in the spinal cord of zebrafish embryos. Development, 146(4), dev172510. https://doi.org/10.1242/dev.172510

Gard, C., Gonzalez Curto, G., Frarma, Y. E.-M., Chollet, E., Duval, N., Auzié, V., Auradé, F., Vigier, L., Relaix, F., Pierani, A., Causeret, F., & Ribes, V. (2017). Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons. Developmental Biology, 432(1), 24–33. https://doi.org/10.1016/j.ydbio.2017.06.014

Theses

Line Manceau – Thesis Defense: 24th September 2021

“Study of the molecular and cellular mechanisms by which the paralogous transcription factors PAX3-FOXO1 and PAX7-FOXO1 exert their oncogenic activity”