Summary: In the formation of the cerebellum, the outer layer cells in a baby’s brain communicate with each other in a unique way using nanotubes. This happens before the synapses are formed.
Source: Institut Pasteur
Over a hundred years after the discovery of the neuron by neuroanatomist Santiago Ramón y Cajal, scientists continue to deepen their knowledge of the brain and its development.
In a publication in Science Advances on April 5, a team from the Institut Pasteur and the CNRS, in collaboration with Harvard University, revealed novel insights into how cells in the outer layers of the brain interact immediately after birth during formation of the cerebellum, the brain region towards the back of the skull.
The scientists demonstrated a novel type of connection between neural precursor cells via nanotubes, even before the formation of synapses, the conventional junctions between neurons.
In 2009, Chiara Zurzolo’s team (Membrane Traffic and Pathogenesis Unit at the Institut Pasteur) identified a novel mechanism for direct communication between neuronal cells in culture via nanoscopic tunnels, known as tunneling nanotubes. These are involved in the spread of various toxic proteins that accumulate in the brain during neurodegenerative diseases.
Nanotubes may therefore be a suitable target for the treatment of these diseases or cancers, where they are also present.
In this new study, the researchers discovered nanoscopic tunnels that connect precursor cells in the brain, more specifically the cerebellum – an area that develops after birth and is important for making postural adjustments to maintain balance – as they mature into neurons.
These tunnels, although similar in size, vary in shape from one to another: some contain branches while others don’t, some are enveloped by the cells they connect while others are exposed to their local environment.
The authors believe these intercellular connections (ICs) may enable the exchange of molecules that help pre-neuronal cells physically migrate across various layers and reach their final destination as the brain develops.
Intriguingly, ICs share anatomical similarities with bridges formed when cells finish dividing.
“ICs could derive from cellular division but persist during cell migration, so this study could shed light on the mechanisms allowing coordination between cell division and migration implicated in brain development.
“On the other hand, ICs established between cells post mitotically could allow direct exchange between cells beyond the usual synaptic connections, representing a revolution in our understanding of brain connectivity.
“We show that there are not only synapses allowing communication between cells in the brain, there are also nanotubes,” says Dr. Zurzolo, senior author and head of the Membrane Traffic and Pathogenesis Unit (Institut Pasteur/CNRS).
To achieve these discoveries, the researchers used a three-dimensional (3D) electron microscopy method and brain cells from mouse models to study how the brain regions communicate between each other. Very high resolution neural network maps could thus be reconstructed. The 3D cerebellum volume produced and used for the study contains over 2,000 cells.
“If you really want to understand how cells behave in a three-dimensional environment, and map the location and distribution of these tunnels, you have to reconstruct an entire ecosystem of the brain, which requires extraordinary effort with twenty or so people involved over 4 years,” said the article’s first author Diego Cordero.
To meet the challenges of working with the wide range of cell types the brain contains, the authors used an AI tool to automatically distinguish cortical layers. Furthermore, they developed an open-source program called CellWalker to characterize morphological features of 3D segments.
The tissue block was reconstructed from brain section images. This program being made freely available will enable scientists to quickly and easily analyze the complex anatomical information embedded in these types of microscope images.
The next step will be to identify the biological function of these cellular tunnels to understand their role in the development of the central nervous system and in other brain regions, and their function in communication between brain cells in neurodegenerative diseases and cancers. The computational tools developed will be made available to other research teams around the globe.
About this neurodevelopment research news
Author: Rebeyrotte Myriam
Source: Institut Pasteur
Contact: Rebeyrotte Myriam – Institut Pasteur
Image: The image is credited to Diego Cordero / Membrane Traffic and Pathogenesis Unit, Institut Pasteur
Original Research: Open access.
“3D reconstruction of the cerebellar germinal layer reveals tunneling connections between developing granule cells” by Chiara Zurzolo et al. Science Advances
Abstract
3D reconstruction of the cerebellar germinal layer reveals tunneling connections between developing granule cells
The difficulty of retrieving high-resolution, in vivo evidence of the proliferative and migratory processes occurring in neural germinal zones has limited our understanding of neurodevelopmental mechanisms.
Here, we used a connectomic approach using a high-resolution, serial-sectioning scanning electron microscopy volume to investigate the laminar cytoarchitecture of the transient external granular layer (EGL) of the developing cerebellum, where granule cells coordinate a series of mitotic and migratory events.
By integrating image segmentation, three-dimensional reconstruction, and deep-learning approaches, we found and characterized anatomically complex intercellular connections bridging pairs of cerebellar granule cells throughout the EGL.
Connected cells were either mitotic, migratory, or transitioning between these two cell stages, displaying a chronological continuum of proliferative and migratory events never previously observed in vivo at this resolution.
This unprecedented ultrastructural characterization poses intriguing hypotheses about intercellular connectivity between developing progenitors and its possible role in the development of the central nervous system.
