Retinal Study Reveals Non-Canonical Neuronal Migration Modes that Orchestrate Concomitant Growth and Differentiation

Abstract

PFIZER RESEARCH AWARDS 2024

Scientific Background

This coordination between growth and differentiation is a hallmark of organogenesis in diverse settings, including the pancreas, liver, heart, and many others. Disruptions in these processes can lead to developmental disorders and structural abnormalities of organs.

This coordination is particularly evident during brain formation, where neuronal migration is a key event, ensuring that newly born neurons reach their correct positions to establish functional circuits. This is necessary, as most neurons are born away from the place where they ultimately function. Neuronal migration in all areas of the brain must be tightly coordinated with concurrent tissue growth and differentiation. Extensive research has been conducted on the role of neuronal migration for cell positioning and circuit formation, mainly in the developing neocortex. Furthermore, many of the cytoskeletal drivers and molecular cascades that guide neuronal migration have been revealed. However, how neuronal migration might contribute to tissue-wide morphogenesis during periods of rapid growth and differentiation is not as well understood. Specifically, it was unknown how migrating neurons and proliferative progenitors avoid spatial competition, ensuring both the establishment of functional architecture and the continued expansion of the tissue.

We used the vertebrate retina, with its conserved architecture across species, as a powerful model to study neuronal migration in the context of overall tissue development. We focused on cone photoreceptor cell migration, as these cells are born relatively early in development, when the tissue is still undergoing substantial proliferation. At the same time, these cells are instrumental for light perception in all vertebrates, including humans. Our model organism of choice was the zebrafish, as this model allows for studying neuronal migration in vivo, while it happens, where it happens. Zebrafish have small, transparent embryos that can be generated in large numbers daily and feature many transgenic lines to mark different cell populations and intracellular components. Another significant advantage of this system is their rapid development, chemical and genetic manipulability. Findings can be generated in a depth hardly possible for any other vertebrate and, in turn, be compared to the human system, either in the form of donated human tissue or newly arising human brain and retinal organoids. We took full advantage of this cross-species comparison in our study, the main findings of which are outlined below.