Description

Recent studies focusing on the role of the cerebrospinal fluid (CSF), a protein rich solution filling the cavities of the central nervous system, have elucidated the importance of an intriguing acellular structure running from the roof of the brain ventricles to the caudal end of the central canal of the spinal cord: the Reissner fiber. This acellular polymer, formed by the self-aggregation of the Sspo glycoprotein secreted into the CSF and conserved in the vertebrate phylum (Meiniel et al. 2008, Journal of Molecular Evolution), was described more than a century ago. Yet, its function remained elusive until recently. The generation of the first sspo mutants in zebrafish (Cantaut-Belarif et al. 2018, Current Biology) revealed that the formation of the Reissner fiber and its correct polymerization along the central canal of the spinal cord is a crucial event controlling the geometry of the embryonic posterior axis. Indeed, sspo mutants develop from 30 hours post-fertilization onwards a peculiar phenotype, fully penetrant, consisting in a downward curvature of the axis connecting the head to the tail of the developing embryo. Interestingly, further observations of juvenile sspo mutants showed that they also develop three dimensional torsions of the spine at juvenile stage, reminiscent of adolescent idiopathic scoliosis arising in human patients during growth spurt (Troutwine et al. 2020, Current Biology ; Rose et al. 2020, Current Biology ; Lu et al. 2020, Biology Open). Thus, mechanisms shaping the geometry of the body axis might share fundamental principles from embryos to juveniles and may rely on a signaling pathway requiring the Reissner fiber in the brain and spinal cord cavities influencing axial straighteninh throughout life .

Using a combination of genetic tools and in vivo imaging in zebrafish embryos, we identified a molecular signature underlying the Reissner fiber-dependent straightening of the body axis. Our investigations showed that the Reissner fiber controls the expression of a neuropeptide expressed in spinal cells contacting the CSF that are involved in axial straightening. In addition, we found that the Reissner fiber binds noradrenergic ligands endogenously present in the embryonic CSF, which are in turn, when provided exogenously, able to tune axial alignment and neuropeptide expression defects in sspo mutants (Cantaut-Belarif et al. 2020, Elife). Yet, the precise mechanisms by which noradrenaline, a catecholamine classically involved in neuromodulation, contributes to the Reissner fiber-dependent morphogenesis of the body during embryonic development are poorly understood.

Our current results (unpublished) indicate that luminal noradrenaline present in the embryonic CSF are integrated in peculiar chemosensory cell targets during axial morphogenesis. This project aims to further characterize the pathway controlled by the Reissner fiber and modulated by luminal signals to ensure a correct morphogenesis of the embryonic body.

During his/her doctoral project, the student will first focus on noradrenergic signaling and: 1/.characterize how multiple cell targets surrounding the central canal of the spinal cord integrate and transduce luminal noradrenaline in the embryo; 2/.identify how the Reissner fiber contributes to the detection and the integration of these signals. Next, he/she will seek to identify whether and how other chemosensory cues present in the embryonic CSF are integrated in the cell targets identified and how their integration might influence axial alignment in the developing embryo.

In this project, the doctoral student will combine genetic approaches and in vivo imaging in the zebrafish embryo. He/she will learn state-of-the-art live imaging techniques and analysis methods, including imaging of genetically encoded sensors and optical manipulations in vivo, coupled to imaging investigations on fixed samples.

Compétences requises

- High motivation and strong background in neurobiology, cell and developmental biology - Strong interest in fluorescence microscopy, and image analysis - Beneficial are expertise in coding, cutting-edge microscopy and zebrafish genetics as well as permit for animal experimental work - Willingness to work in a multidisciplinary team - Good English oral and writing skills

Bibliographie

-Meiniel et al., 2008, Journal of Molecular Evolution, 'The lengthening of a giant protein: When, how, and why?', doi: 10.1007/s00239-007-9055-3
- Cantaut-Belarif et al., 2018, Current Biology, 'The Reissner fiber in the cerebrospinal fluid controls morphogenesis of the body axis.' doi: 10.1016/j.cub.2018.05.079.
- Troutwine et al. 2020, Current Biology, 'The Reissner fiber is highly dynamic in vivo and controls morphogenesis of the spine.' doi: 10.1016/j.cub.2020.04.015
- Rose et al. 2020, Current Biology, 'SCO-Spondin defects and neuroinflammation are conserved mechanisms driving spinal deformity across genetic models of idiopathic scoliosis.' doi: 10.1016/j.cub.2020.04.020
- Lu et al. 2020, Biology Open, 'Reissner fibre-induced urotensin signalling from cerebrospinal fluid-contacting neurons prevents scoliosis of the vertebrate spine.' doi: 10.1242/bio.052027
- Cantaut-Belarif et al., 2020, Elife, 'Adrenergic activation modulates the signal from the Reissner fiber to cerebrospinal fluid contacting neurons during development.' doi: 10.7554/Elife.59469.

Mots clés

Morphogénèse axiale, Liquide cérébrospinal, Fibre de Reissner, Poisson-zèbre, Développement embryonnaire, Imagerie in vivo