Group leader: Sophie Creuzet

Development & Evolution of the Neural Crest (DENC)

In brief

The neural crest, a unique cell population originating from the primitive neural field, has a multi-systemic and structural contribution to vertebrate development. At cephalic level, the neural crest generates most of the skeletal tissues encasing the developing forebrain and provides the prosencephalon with functional vasculature and meninges.

Over the last decade, we have demonstrated that the cephalic neural crest (CNC) exerts an autonomous and prominent control on forebrain and sense organs development. Some of the molecular determinants regulators required to convey this morphogenetic effect have been identified.

These notions of exogenous patterning sources of the forebrain and CNS provide a novel conceptual framework: they have profound implications in Developmental Biology. From biomedical standpoint, these data also suggest that the spectrum of neurocristopathies is broader that expected and that some rare diseases including neurological disorders, which are multi-factorial and polygenic, may stem from CNC dysfunctions.

By using exquisite grafting experiments in combination with focal spatially and temporally controlled transgenesis, we have discovered the unexpected and potent “paracrine” role that the CNC exerts on forebrain growth and patterning early in development and documented this mechanism at the level of cell interaction, signaling and gene expression. This notion has broken the traditional view of how the brain develops and has profound implication Developmental Biology. It shows that the CNC beyond its skeletal vascular and meningeal contribution to forebrain development, itself acts as a “ dorsalizing brain organizer ”.

We are now following this exiting line of research, which revisits fundamental concepts in Neurosciences. Our ongoing project aims at understanding and documenting how the dysfunctions of CNC cells, and the meninges they form, could affect the development of the intracerebral vascular network and brain homeostasis, and cause neurodevelopmental defects associated with the behavioral impairment. The mechanisms identified so far in our model are conserved across tetrapodes, but some social behavioural features are specific to amniotes. This notion provides a conceptual renewal, which is also bio-medically relevant. Our data, suggest that some neurological disorders, which are multi-factorial and polygenic, may stem from CNC dysfunctions. Our project and future directions are to explore the etiology of neural disorders and behavioral impairments in the light of CNC dysfunctions.

Selected publications

  • Alrajeh M, Vavrusova Z, Creuzet SE. (2019) ; Deciphering the Neural Crest Contribution to Cephalic Development with Avian Embryos. Methods Mol Biol. 2019;1976:55-70. DOI: 10.1007/978-1-4939-9412-0_5
  • Cavodeassi F., Creuzet S., Etchevers H. (2018). The hedgehog pathway and ocular developmental anomalies. Human Genetics, DOI: 10.1007/s00439-018-1918-8
  • Acuna-Mendoza S, Martin S, Kuchler-Bopp S, Ribes S, Thalgott J, Chaussain C, Creuzet S, Lesot H, Lebrin F, Poliard A. (2017). A New Wnt1-CRE TomatoRosa Embryonic Stem Cell Line: A Tool for Studying Neural Crest Cell Integration Capacity. Stem Cells Dev. 2017 Nov 3. DOI: 10.1089/scd.2017.0115
  • Creuzet, S. E. and Etchevers, H. C. (2017). Embryologie de l’œil humain. In Ophtalmologie pédiatrique .Elsevier-Masson. DOI: 10.6084/m9.figshare.4983362.v1
  • Creuzet S., Viallet J., Ghawitian M. , Thélu J., ALrajeh M., Costagliola F., Le Borgne M., Buchet-Poyau K., Aznar N., Buschlen S., Hosoya H., Thibert C., and Billaud M. (2016). LKB1 signaling in cephalic neural crest is essential for vertebrate head development. Develomental Biology. 418(2):283-96. DOI: 10.1016/j.ydbio.2016.08.006
  • Couesnon A., Lindovsky J., Zakarian A., Creuzet S., and Molgo J. (2014). Pinnatoxins block skeletal neuromuscular junction activity and affect embryo development. Toxicon, 91, 175-176. DOI: 10.1016/j.toxicon.2014.08.036
  • Cajal M., Creuzet S.E., Papanayotou C., Sabéran-Djoneidi D., Chuva de Sousa Lopes S., Zwijsen A., Collignon J., and Camus A. (2014). A conserved role for non-neural ectoderm cells in early neural development. Development. 141(21):4127-38. DOI: 10.1242/dev.107425
  • Aguiar D.P., Sghari S., and Creuzet S.E (2014) .The facial neural crest controls fore- and midbrain pattering by regulating Foxg1 expression through Smad1 activity. Development, 141, 2494-2505. DOI: 10.1242/dev.101790
  • Garcez R. C., Le Douarin N. M., and Creuzet S. E. (2014). Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development. Cell Molecular Life Sciences, 71, 2149-2164. DOI: 10.1007/s00018-013-1477-z
  • Cases O., Perea-Gomez A, Aguiar D.P., Nykjaer A., Lelièvre V., Amsellem S., Chandellier J., Pedersen G., Cereghini S., Collignon J., Verroust P., Umbhauer M., Madsen M., Riou J.F., Creuzet S.E. and Kozyraki R. (2013). Cubilin is required for FgF-promoted cell survival in the developing vertebrate head. J Biol Chem, 288, 16655-16670. DOI: 10.1074/jbc.M113.451070
2023

  • Diego Amarante-Silva, Emmanuel Bruet, Rémy Gars, Margaux Piechon, Tatiana Gorojankina, Jérôme Bignon, Sophie Creuzet (2023).Neural crest mural cells of forebrain meninges harbor innate immune functions during early brain development and exhibit different responses to septic and toxic insults. Preprints.org, doi: 10.1101/2023.11.28.569020
  • Emmanuel Bruet, Diego Amarante-Silva, Tatiana Gorojankina, Sophie Creuzet (2023).The Emerging Roles of the Cephalic Neural Crest in Brain Development and Developmental Encephalopathies. International Journal of Molecular Sciences, 24 (12), pp.9844. doi: 10.3390/ijms24129844
  • Alexandra Vargas, Clemence Guillermain, Tatiana Gorojankina, Sophie Creuzet (2023). Heterospecific developmental models highlight the role of FBXO32 in neural crest lineages and the significance of its variant in pediatric melanoma. BioRxiv, doi: 10.1101/2023.03.10.532100

2020

  • Denis Servent, Sophie Creuzet, Carole Malgorn, Vincent Dive, Armen Zakarian, Jordi Molgó. (2020). Pinnatoxins, an emergent class of marine toxins interacting with nAChRs. Pharmacological characterization, biodistribution and musculo-skeletal effect of these neurotoxic agents.Toxicon. 177:S3. doi: 10.1016/j.toxicon.2019.10.015

2019

  • Cavodeassi F., Creuzet S., Etchevers H. (2019). The hedgehog pathway and ocular developmental anomalies. Human Genetics 138:917–936 (2019), doi: 10.1007/s00439-018-1918-8
  • Moussab Alrajeh, Zuzana Vavrusova, Sophie Creuzet (2019). Deciphering the Neural Crest Contribution to Cephalic Development with Avian Embryos. Methods Mol Biol. 1976:55-70 (2019), doi: 10.1007/978-1-4939-9412-0_5

2017

  • Acuna-Mendoza S, Martin S, Kuchler-Bopp S, Ribes S, Thalgott J, Chaussain C, Creuzet S, Lesot H, Lebrin F, Poliard A. (2017). A New Wnt1-CRE TomatoRosa Embryonic Stem Cell Line: A Tool for Studying Neural Crest Cell Integration Capacity. Stem Cells Dev. 2017 Nov 3. doi: 10.1089/scd.2017.0115
  • Creuzet, S. E. and Etchevers, H. C. (2017). Embryologie de l’œil humain. In Ophtalmologie pédiatrique .Elsevier-Masson. doi: 10.6084/m9.figshare.4983362.v1

2016

  • Creuzet S., Viallet J., Ghawitian M. , Thélu J., ALrajeh M., Costagliola F., Le Borgne M., Buchet-Poyau K., Aznar N., Buschlen S., Hosoya H., Thibert C., and Billaud M. (2016). LKB1 signaling in cephalic neural crest is essential for vertebrate head development. Develomental Biology. 418(2):283-96. doi: 10.1016/j.ydbio.2016.08.006

2014

  • Couesnon A., Lindovsky J., Zakarian A., Creuzet S., and Molgo J. (2014). Pinnatoxins block skeletal neuromuscular junction activity and affect embryo development. Toxicon, 91, 175-176
  • Cajal M., Creuzet S.E., Papanayotou C., Sabéran-Djoneidi D., Chuva de Sousa Lopes S., Zwijsen A., Collignon J., and Anne Camus (2014). A conserved role for non-neural ectoderm cells in early neural development. Development . Sous presse.
  • Aguiar D.P., Sghari S., and Creuzet S.E (2014) .The facial neural crest controls fore- and midbrain pattering by regulating Foxg1 expression through Smad1 activity. Development, 141, 2494-2505. PMID : 24917504.
  • Garcez R. C., Le Douarin N. M., and Creuzet S. E. (2014). Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development. Cell Mol. Life Sci., 71, 2149-2164. PMID : 24061537.

2013

  • Cases O., Perea-Gomez A, Aguiar D.P., Nykjaer A., Lelièvre V., Amsellem S., Chandellier J., Pedersen G., Cereghini S., Collignon J., Verroust P., Umbhauer M., Madsen M., Riou J.F., Creuzet S.E. and Kozyraki R. (2013). Cubilin is required for FgF-promoted cell survival in the developing vertebrate head. J. Biol. Chem., 288, 16655-16670. doi : 10.1074/jbc.M113.451070.

2012

  • Le Douarin N.M., Couly G., and Creuzet S.E. (2012) The neural crest is a powerful regulator of pre-otic brain development. Dev. Biol., 366, 74-82.

2011

  • Le Douarin N.M. and Creuzet S. (2011). Neural crest and Vertebrate evolution. Biol Auj. 205 (2), 87-94.

2009

  • Creuzet S.E. (2009) Regulation of pre-otic brain development by the cephalic neural crest. Proc. Natl Acad. Sci. USA, 106, 15774-15779.
  • Creuzet S. E. (2009). Neural Crest Contribution to Forebrain Development. Book chapter In Development of Patterning of the Vertebrate Forebrain. Sem. Cell and Dev. Biol., 20, 751-759.
  • Le Douarin N.M. and Creuzet S.E (2009). Craniofacial patterning. Book Chapter. In The Skeletal System. Cold Spring Harbor Laboratory Press, 53, 117-147 (ISBN 978-087969825-6).
  • Creuzet S. (2009). Neural crest contribution to forebrain development and morphogenesis. Mech Dev, 126, S101.

2008

  • Le Douarin N., Dieterlen-Lièvre F., Creuzet S. and Teillet M.-A. (2008). Quail–Chick Transplantations. Book Chapter. Methods in Cell Biology, 87, 19-58.

2007

  • Le Douarin, N.M., Brito J.M., and Creuzet S. (2007). The role of the neural crest in face and brain development. Brain Res. Reviews, 55,237-247.
  • Charrier J.B. et Creuzet S. (2007). Embryologie de la face et dysplasies otomandibulaires. Ortho. Fr., 78, 3-20.

2006

  • Creuzet S., Martinez S., and Le Douarin N. M. (2006). The cephalic neural crest exerts a critical effect on forebrain and midbrain development. Proc. Natl. Acad.Sci. USA., 103, 14033-14038.
  • Dupin E., Creuzet S. and Le Douarin N.M. (2006) “The contribution of the neural crest to the vertebrate body“. Book chapter. In Neural Crest Induction and Differentiation J.P. Saint-Jeannet, ed. Landes Biosciences, Austin, TX (ISBN 0-387-35136-1).

2005

  • Dieterlen-Lièvre F., Creuzet S. and Salaün J. (2005). “In vivo methods to analyse cell origins, migration, homing and interactions in the blood, vascular, and immune system of the avian and mammalian embryo“. Book chapter. In Developmental Hematopoiesis. Methods and Protocols. Methods in Molecular Medicine, 105, 215-229. Humana Press, Totowa, NJ.
  • Creuzet S., Couly G., and Le Douarin N.M. (2005) Patterning the neural crest derivatives during the development of the vertebrate face : insights from avian studies. J. Anatomy, 207, 447-459.
  • Creuzet S., Vincent C., and Couly G. (2005). Neural crest derivatives in ocular and periocular structures. Int. J. Dev. Biol. 49, 161-171.

2004

  • Creuzet S., Schuler B., Couly G., and Le Douarin N. M. (2004). Reciprocal relationships between Fgf8 and neural crest cells in facial and forebrain development. Proc. Natl. Acad. Sci. USA. 101, 4843-4847.
  • Le Douarin N.M., Creuzet S., Couly G. (2004). Neural crest cell plasticity and its limits. Development, 131, 4637-4650.
  • Le Douarin N.M., Creuzet S., Couly G., and Dupin E. (2004). Neural crest cell plasticity and its limits. Development, 131, 4637-4650.