The mammalian brain develops through a complex interplay of spatial cues. These cues are generated by diffusible morphogens, cell-to-cell interactions, and intrinsic genetic programs that result in probably more than a thousand distinct cell types.
Understanding this process requires a systematic characterization of cell states. Understanding how hundreds of disparate cell types arise has proven difficult, mainly because scientists have lacked the technologies to capture cellular decision-making over time.
Recent advances have permitted scientists to gauge changes in gene activity of individual cells of the brain, so a few groups began to concentrate exhaustively on how specialized cell types are shaped in specific brain regions. Although, no one had so far traced the examples of gene expression across the whole developing brain.
Now, for the first time, EPFL researchers and their collaborators at Karolinska Institute in Sweden mapped the genetic and developmental trajectories that embryonic cells follow toward their fate in the maturing brain.
Study lead author Gioele La Manno, head of the Laboratory of Neurodevelopmental Systems Biology at EPFL, said, “This molecular atlas could not only help better understand the healthy and diseased brain but also improve therapeutic approaches such as cell replacement therapy for neurodegenerative diseases.”
Scientists analyzed brain samples from mouse embryos every day from day 7 after fertilization until birth. They did this to monitor decision-making in individual cells over time. With the help of powerful sequencing techniques and mathematical methods, scientists obtained about 290’000 gene expression profiles of individual cells from all brain regions. They also obtained almost 800 cellular ‘states’ included in the developmental programs for different cells, including neurons and neuronal support cells.
As neuronal progenitors develop, they quit proliferating and differentiate into scores of various neurons. They tracked the emergence of this diversity and described the timing of appearance of primitive nerve cells, called neuroblasts, across different brain regions.
Neuroblasts in mice appear before the 9th day of embryonic development. These pioneer neurons are involved in sensory and motor functions.
La Manno said, “One of the first things to do is to set up the motor and sensory functions because if you don’t set these up early, later on, it will become more difficult to build ‘highways’ towards the periphery.”
Scientists also found a specific type of neuronal progenitors, called organizer radial glial cells. The role of these progenitors is to produce molecular messengers and direct the development of neighboring cells. The molecular messengers establish the position of various specialized cell types within the brain.
La Manno said, “If the brain were an orchestra, organizer radial glial cells would be the director. These radial glial cells produce a greater variety of molecular messengers than scientists thought.”
This detailed study enabled scientists to identify cell populations of different sizes, with some populations made of 100 times more cells than others. One such biggest population of excitatory neurons lies in the forebrain. On the other hand, the smallest people identified were a type of neuronal support cell called ependymal cells.
La Manno said, “The wealth of information contained in this brain atlas could help identify genes involved in neurodevelopmental conditions and determine the origin of malignant cells in brain cancer. The atlas could also serve as a reference to evaluate brain tissues generated from stem cells in a laboratory dish.”
“We are planning to uncover wherein the developing brain the different cell populations are located. The current atlas is a molecular chart that tells you which kinds of cells are similar and which ones are different. Now, we want to see where these cells sit within the brain.”
- La Manno, G., Siletti, K., Furlan, A. et al. Molecular architecture of the developing mouse brain. Nature (2021). DOI: 10.1038/s41586-021-03775-x