PROJECT 4
Intrinsic mechanisms that drive axon guidance at the optic chiasm
Why?
Precise connectivity between the retina and the brain is crucial for the processing of visual information by the nervous system. In the eye, retinal ganglion cells (RGCs) are the only projection neurons that collect visual information from the retina and relay it to the brain. Developing RGC axons en route for their brain targets take important guidance decisions at the optic chiasm: crossing or avoiding the midline to connect the contra- or ipsilateral brain hemisphere, respectively. Accurate navigation of RGC axons at the chiasm is thus critical for the shaping of neuronal connectivity that forms the basis of binocular vision. Its dysfunction not only contribute to the physiopathology of human congenital disorders (e.g. albinism, achiasma) but also represents a major barrier to the success of regenerative/cellular therapies aiming at restoring functional visual connectivity following optic nerve injury or RGC degeneration (e.g. Glaucoma). The molecular cues that guide RGC axons at this major decision point are mostly known. However, our understanding of the intrinsic mechanisms that adapt RGC growth cone behaviors to these guidance cues is far from being complete. In this context, our team identified the multifaceted microtubule-depolymerizing ATPase fidgetin-like 1 as key player in vertebrate neuronal circuit wiring. Our preliminary proteomic and in vivo data suggest that fidgetin-like 1 behaves as an integrator and regulator of the Slit/Robo guidance pathway required for accurate retinal axon guidance along the optic pathway.
How?
This PhD project will use an original combination of biological systems (in vitro cell-free systems, mammalian retinal explants and in vivo genetic approaches in the zebrafish), Omics approaches (scRNA seq, global proteomic approaches) and cutting-edge imaging technologies to dissect the role of Fignl1 in Slit/Robo-evoked retinal axon guidance. The relevance of this data for human retinal axon guidance will be assessed in retinal ganglion cell derived from human iPSC in collaboration with the lab of Arthur Bergen (Amsterdam UMC). Altogether, this PhD project will uncover novel key players in visual circuit wiring that could represent relevant therapeutic targets to promote directed axon (re)growth to (re)establish functional visual connectivity in pathological conditions.
What can you expect?
The successful candidate will be gain expertise in molecular and cellular neurodevelopmental biology. She/He will be trained for in vivo genetic approaches in the zebrafish, cell culture, in vivo and in vitro live imaging, optogenetics, cutting-edge microscopy, , and retinal organoids. In addition, she/he will benefit from the training activities scheduled by the EGRET-AAA program (workshops, meetings, …).
Where?
This project is a joint-doctorate between the Vision Institute (Sorbonne University, Paris; www.xaviernicol.toile-libre.org; www.institut-vision.org) and the Amsterdam UMC. The trainee will be hosted by the Vision Institute where she/he will join the Nicol lab, under supervision of Dr. Coralie Fassier. The Vision Institute offers the entire infrastructure required to conduct this project: the aquatic, cell culture, biochemistry facilities as well as cutting-edge microscopy setups for live imaging in zebrafish embryos and retinal explants. Furthermore, she/he will conduct a secondment project in the Bergen lab (Amsterdam UMC), under supervision of prof. Arthur Bergen, where the equipment and expertise in generating retinal organoids are available.
Who are we looking for?
We are looking for a highly motivated, dynamic and talented student who enjoys teamwork and has strong communication and interpersonal skills. The successful candidate must hold a Neuroscience or Cell Biology Master (other Master programs will be considered as well) by the end of the 2022-2023 academic year. Fluency in English is mandatory but ability to speak French is not required.
References
- Motor axon navigation relies on Fidgetin-like 1-driven microtubule plus end dynamics. Fassier C et al. J Cell Biol. 2018. doi.org/10.1083/jcb.201604108
- FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation. Atkins M et al. J Cell Biol. 2019. doi.org/10.1083/jcb.201805128
- An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development. Wagstaff PE, et al. Sci Rep. 2021. doi.org/10.1038/s41598-020-79651-x