L'origine des asymétries épithalamiques chez les vertébrés: mécanismes de formation chez la lamproie de rivière // The origin of epithalamic asymmetries in vertebrates: cellular and mechanistic analysis in the river lamprey

The vertebrate epithalamus consists of the habenulae, a bilateral structure, the pineal organ and in some species, a parapineal accessory organ. A remarkable feature of the habenulae is that in many species, belonging to all major vertebrate groups, they exhibit asymmetries between their left and right sides (Concha and Wilson, 2001). These asymmetries vary extensively, in nature and degree, leaving unanswered the question of their mode of evolution. Genome-wide molecular characterizations, conducted thus far in only two jawed vertebrates, the catshark (cartilaginous fish) and the zebrafish (ray-finned fish) highlight an extensive divergence of habenular asymmetries in the adult organ (Lanoizelet et al., 2024). Unexpectedly in view of this divergence, functional analyses of the mechanisms underlying their formation reveal a similar involvement of Wnt signaling, repressed on the left side in both species. However, this left repression of Wnt activity results from different upstream regulations between the two species, being parapineal-dependent and Nodal-independent in the zebrafish and on the contrary, parapineal-independent but Nodal-dependent in the catshark (Lagadec et al., 2015). The cellular mechanisms regulated by the Wnt pathway also differ between the zebrafish and the catshark. In the zebrafish, Wnt signaling promotes right identities in the dorsal habenula by an asymmetric temporal regulation of neurogenesis, delayed on the right side relative to the left one (Hüsken et al., 2014; Guglielmi et al., 2020). In the catshark, the conservation of this mechanism remains unclear, with Wnt signaling promoting a right-sided neuronal identity choice in post-mitotic neuronal precursors in another habenular territory (lateral habenulae) (Lanoizelet et al., 2024). While these data support an ancient involvement of Wnt signaling in the formation of habenular asymmetries, the taxa-specific diversifications resulting in these mechanistic divergences remain unclear. To resolve this issue, we propose to conduct a phylogenetic approach, aimed at reconstructing ancestral roles of Wnt signaling in the formation of habenular asymmetries and inferring taxa-specific divergences from this reference. To do so, the work will concentrate on the river lamprey. As a member of cyclostomes, the sister group of jawed vertebrates, this species occupies a key phylogenetic position to identify ancestral mechanisms controlling habenular asymmetry formation. Importantly, the lamprey exhibits similarities in habenula organization both with the catshark and the zebrafish, suggesting differential retention of ancestral asymmetry traits in these two species. Furthermore, we have already reported an asymmetric nuclear distribution of beta-catenin in the developing lamprey habenulae, which supports a conserved involvement of Wnt signaling in this process (Guichard et al., 2025). The project aims at deciphering the cellular and molecular roles of Wnt signaling in the development of habenular asymmetries in prolarval and larval lamprey habenulae, using a combination of complementary approaches, including analysis of the timing of neurogenesis and of the elaboration of neuronal cell identities on the left and the right sides as well as functional analyses of the Wnt pathway. We will use both well-established experimental and molecular approaches routinely used in the laboratory, such as in situ hybridization (ISH), hybridization chain reaction ISH, BrdU/EdU incorporation assays, immunohistochemistry, pharmacological inactivation of the Wnt pathway, as well as more advanced ones, like single nuclei RNA-seq and CRISPR-cas9-based gene editing. The data obtained in the course of this project will provide a clear picture of the sequential roles of Wnt signaling in the formation of habenular asymmetries, representing an essential reference to retrace the phylogenetic history of this trait in vertebrates.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------------------------------

The vertebrate epithalamus consists of the habenulae, a bilateral structure, the pineal organ and in some species, a parapineal accessory organ. A remarkable feature of the habenulae is that in many species, belonging to all major vertebrate groups, they exhibit asymmetries between their left and right sides (Concha and Wilson, 2001). These asymmetries vary extensively, in nature and degree, leaving unanswered the question of their mode of evolution. Genome-wide molecular characterizations, conducted thus far in only two jawed vertebrates, the catshark (cartilaginous fish) and the zebrafish (ray-finned fish) highlight an extensive divergence of habenular asymmetries in the adult organ (Lanoizelet et al., 2024). Unexpectedly in view of this divergence, functional analyses of the mechanisms underlying their formation reveal a similar involvement of Wnt signaling, repressed on the left side in both species. However, this left repression of Wnt activity results from different upstream regulations between the two species, being parapineal-dependent and Nodal-independent in the zebrafish and on the contrary, parapineal-independent but Nodal-dependent in the catshark (Lagadec et al., 2015). The cellular mechanisms regulated by the Wnt pathway also differ between the zebrafish and the catshark. In the zebrafish, Wnt signaling promotes right identities in the dorsal habenula by an asymmetric temporal regulation of neurogenesis, delayed on the right side relative to the left one (Hüsken et al., 2014; Guglielmi et al., 2020). In the catshark, the conservation of this mechanism remains unclear, with Wnt signaling promoting a right-sided neuronal identity choice in post-mitotic neuronal precursors in another habenular territory (lateral habenulae) (Lanoizelet et al., 2024). While these data support an ancient involvement of Wnt signaling in the formation of habenular asymmetries, the taxa-specific diversifications resulting in these mechanistic divergences remain unclear. To resolve this issue, we propose to conduct a phylogenetic approach, aimed at reconstructing ancestral roles of Wnt signaling in the formation of habenular asymmetries and inferring taxa-specific divergences from this reference. To do so, the work will concentrate on the river lamprey. As a member of cyclostomes, the sister group of jawed vertebrates, this species occupies a key phylogenetic position to identify ancestral mechanisms controlling habenular asymmetry formation. Importantly, the lamprey exhibits similarities in habenula organization both with the catshark and the zebrafish, suggesting differential retention of ancestral asymmetry traits in these two species. Furthermore, we have already reported an asymmetric nuclear distribution of beta-catenin in the developing lamprey habenulae, which supports a conserved involvement of Wnt signaling in this process (Guichard et al., 2025). The project aims at deciphering the cellular and molecular roles of Wnt signaling in the development of habenular asymmetries in prolarval and larval lamprey habenulae, using a combination of complementary approaches, including analysis of the timing of neurogenesis and of the elaboration of neuronal cell identities on the left and the right sides as well as functional analyses of the Wnt pathway. We will use both well-established experimental and molecular approaches routinely used in the laboratory, such as in situ hybridization (ISH), hybridization chain reaction ISH, BrdU/EdU incorporation assays, immunohistochemistry, pharmacological inactivation of the Wnt pathway, as well as more advanced ones, like single nuclei RNA-seq and CRISPR-cas9-based gene editing. The data obtained in the course of this project will provide a clear picture of the sequential roles of Wnt signaling in the formation of habenular asymmetries, representing an essential reference to retrace the phylogenetic history of this trait in vertebrates.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Début de la thèse : 01/10/2026
WEB : https://biom.obs-banyuls.fr/equipe-developpement-evolution-vertebres/

Public funding alone (i.e. government, region, European, international organization research grant)

Concours pour un contrat doctoral - SU

Sorbonne Université SIS (Sciences, Ingénierie, Santé)

515 Complexité du vivant

Mastère 2 Formation solide en biologie du développement, biologie cellulaire et génétique Compréhension des concepts de base en évolution Expérience pratique en biologie moléculaire, histologie, manipulation d'embryons Formation théorique en transcriptomique (bulk, noyaux uniques, spatiale), notions de bases sur leurs méthodes d'analyse
Master 2 Strong background in developmental biology, cellular biology and genetics Basic understanding of the concepts of evolution Practical experience in molecular biology, histology, embryo manipulation Theoretical background in transcriptomics (bulk RNA-seq, snRNA-seq, spatial transcriptomics), basic understanding of related data analyses