Title: Role of filopodia in multipolar neuronal navigation
Supervisors: Jaakko Lehtimäki and Caren Norden
IGC Group: Cell Biology of Tissue Morphogenesis
E-mail contact: [email protected]
Preferred date of start: Possible to start from 01/03/2023 onwards
Abstract: The orchestration of neurons into functional layers, is the key event in brain development. As neurons are often born away from where they later function, they need to migrate to their correct positions. To date, we have a general understanding on radial and tangential migration modes where neurons with defined polarity use extracellular matrix and other neuronal processes as tracks. However, much less is known about how neurons moving in a multipolar fashion and frequently change their direction and extend long, seemingly randomly oriented filopodia, find their correct location and how they interpret what type of environmental signals. This is important as multipolar neurons play a prominent role in the formation of different parts of the central nervous system (CNS). Our overarching objective is thus to understand the cell- and tissue-derived factors neurons undergoing multipolar migration use to navigate.
To investigate this, we study multipolar neurons, named horizontal cells (HC), in the developing zebrafish retina. The transparent vertebrate retina is the most accessible part of the CNS that undergoes fascinating transformation from a pseudostratified epithelium into ordered and layered assembly of five retinal cell types. In zebrafish, the whole process is complete within 72 hours post fertilization. Differentiating HCs engage into multipolar migration extending multiple filopodial protrusions to travel through the developing retina. They take very heterogeneous paths to reach their final destination and migrate in an ECM-free environment. These findings suggest that cell/tissue-derived guidance cues could be guiding the HC migration. To support this, we are analysing a recently generated transcriptomics dataset providing a list of candidate genes expressed in HCs or in other retinal neurons that could act as a secreted or contact-mediated guidance molecules for the HCs.
During this project, you will investigate if filopodia, generally known to act as a “a sensory organs” for the cell, are used by HCs to a) probe for the surrounding guidance cues and / or b) find the path of least resistance through other cells inhabiting the developing retina, to reach their final location. Your toolbox will include state-of-the -art techniques for in vivo imaging of HCs’ filopodia e.g., light-sheet-, super-resolution-, and expansion microscopy. You have the chance to generate knockout embryos to analyse if or how HCs lacking filopodia navigate and potentially extend these observations by comparing HCs in vivo vs. in vitro cultures. Unveiling the role of filopodia in multipolar neuronal migration, will provide important insights into the in vivo mechanisms of similar migratory patterns observed also in other developing brain areas.
We are seeking highly motivated, organized applicant to conduct this cutting-edge research project on cell-tissue interplay in neuronal migration. Background in developmental and cell biology as well as experience in in vivo / in vitro imaging, is considered a plus as is experience with model organisms. However, motivation and curiosity are the main selection criteria.