Créé(e) 12/10/2022 Mis à jour 07/11/2022
28 oct
2022
[Soutenance de HDR de Agnès Boutet ] Two decades of work in developmental biology and Evo-Devo leading to questions about renal stem cells and kidney regeneration in Chondrichthyes.

SoutenanCE DE HDR , le 28 oct. A 9H00 en salle de CONFERENCES DE LA STATION BIOLOGIQUE DE ROSCOFF

 

membres du jury 

Alice Davy (Reviewer)

Christoph Englert (Examiner)

Andreas Hejnol (Reviewer)

Pascal Houillier (Reviewer)

Sophie Saunier (Examiner)

Muriel Umbhauer (Examiner)

 

This manuscript covers more than twenty years of research in developmental biology carried out during my two post-doctorates and since I took up my permanent position in Roscoff in 2011. In the first part (part I), I am presenting works related to the role of the developmental gene Snail1 and the tumour suppressor gene WTX in embryogenesis and human renal diseases. We could demonstrate that Snail1, an important inducer of the epithelial to mesenchymal transition (EMT), is expressed during kidney ontogenesis but that it must remain silent in the adult organ. More importantly, experimentally-induced renal fibrosis can be hampered when Snail1 expression is blocked. As for WTX, it has been described to be mutated in a paediatric renal cancer, the Wilms tumour and in a bone malformation syndrome. We showed that WTX and its two paralogues are present only in vertebrate species indicating that these genes are novel inventions that originated early in vertebrate evolution. We also generated a novel mouse line that allows ectopic and conditional expression of Wtx fused to GFP, the R26floxneoGFPWtx mouse, in a Cre recombinase driven tissue specific manner. Importantly, constitutive activation of the R26floxneoGFPWtx allele is able to rescue the skeletal phenotypes observed in the Wtx KO mice.

In the second part (part II), I am presenting the model I am using now in Roscoff for my research, the catshark S. canicula. It belongs to Chondrichythes (cartilaginous fish), the sister group of Osteichythyes (bony vertebrates), a phylogenetic position that allows its use to address Evo-Devo questions. More particularly, we have demonstrated that asymmetry of a brain structure called the epithalamus in the catshark is controlled by the morphogen Nodal while in teleosts, Nodal rather controlled laterality of the epithalamus. In a subsequent review, I questioned the origin of the epitalamus in vertebrates and reviewed the role of Nodal as a symmetry breaker across metazoans.

The catshark is not only a model in Evo-Devo. As other adult cartilaginous fish, it displays the property to grow new nephrons, the functional units of the kidney. This ability has been lost in mammals making the catshark a striking animal to understand this process of regeneration. This is the topic of my current research exposed in the third part of this manuscript (part III). During embryogenesis, all the epithelial cells of the nephrons differentiate from a pool of mesenchymal cells (renal progenitors) that have been highly characterized in mice. In mammals this pool is exhausted at birth but persists in adult cartilaginous fish. We aim to characterize the catshark renal progenitors during the transition from embryogenesis to juvenile stage using a spatial transcriptomic approach. More precisely we will focus on changes affecting translational control and the mTOR signalling, a central pathway in translation initiation. Indeed, several adult stem cell populations have been previously demonstrated to be dependent on low protein synthesis rates to maintain an undifferentiated states. In addition, we synthesized in a recent review the mechanistic implications of the mTOR signalling in a wide range of metazoan regeneration processes highlighting how this pathway could be targeted in human diseases to induce regrow and repair of missing tissue. Our goal is thus to identify mTOR pathway regulators allowing the renal mesenchymal progenitors to be maintained in the adult catshark. This will contribute to the development of strategies focused on the reactivation of kidney regeneration in the adult mammalian kidney.