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Developmental Biology - Cell Differentiation
Deciphering the Cerebral Cortex
Researchers unravel mechanisms controlling cell differentiation...
The cortex is a complex brain region shaping how we perceive and interact with objects in the world around us. The diversity of these tasks is reflected in the variety of neurons making up the cortex. Several dozen cell types, each with distinct functions, come together during embryo formation to make countless circuits shaping our basic to complex thoughts and actions.
Neurons spawn from progenitor stem cells, which divide to produce different cell types which handle each reaction and response. But how do these progenitor cells manage to generate specific types of neurons in the right place at the right time?
Through observation and identification of genetic scenarios at work, researchers from Geneva (UNIGE), Lausanne (UNIL), Switzerland, and Liège (ULiège), Belgium, help lift the veil on how cell differentiation leads to brain circuits. Their results, published in the journal Science, also provide a deeper explanation for the origin of neurodevelopmental disorders.
During embryogenesis, different neurons are generated by progenitor cells in the depths of the brain. These neurons then assemble to form circuits that control movement or perception.
"We had already studied the bioelectrical properties of progenitor (cells) in order to identify subtle processes governing cell differentiation. But what about genetics? Which genes control the delicate balance between innate and acquired programmes? This is what we wanted to understand here."
Denis Jabaudon PhD, professor, Department of Basic Neurosciences, UNIGE Faculty of Medicine, and team leader.
Newborn neurons not only inherit genetic material from the 'mother' cell, but also develop their own genetic programs through interaction with their environment. This maturation process ultimately connects neurons into functional circuits.
Precise time patterns
Together with Ludovic Telley, Professor, UNIL Faculty of Medicine, Biology, and Gulistan Agirman, doctoral student at GIGA-Stem Cells, ULiège, Denis Jabaudon's team systematically followed genes expressed by successive generations of progenitor and daughter cells — with a very high temporal resolution. Taking advantage of a technology developed at UNIGE that isolates cortical cells born at a specific time, researchers were able to reconstruct a genetic scenario by which progenitor cells give birth to neurons of different types.
"We then developed mathematical algorithms to reconstruct the generation of neurons," explains Ludovic Telley.
"This allowed us to observe the essential roles of certain genes transmitted by mother progenitor cells. As proof, by artificially modifying these time marks in the progenitors, we succeeded in changing the identity of daughter neurons and accelerating the speed of development," adds Gulistan Agirman.
Indeed, if, at the very beginning, progenitor cells are not very sensitive to environmental signals — they become more and more so over time.
These temporal patterns of gene expression are then transmitted by progenitor cells to their offspring. "As proof, by artificially modifying these time marks in the progenitors, we have succeeded in changing the identity of daughter neurons and accelerating the speed of the developmental scenario," says Gulistan Agirman.
The origin of neurodevelopmental disorders?
These studies, based on a mouse model, also apply to human beings. By studying human biological data, the team was able to show that time marks — along with their genetic transmission mechanisms — were conserved during evolution.
This important discovery highlights the importance of temporal genes in the generation of cerebral cortex circuits, and identifies genetic programs whose alteration could contribute to neuro-developmental diseases. In addition, this study may identify "molecular recipes" to be applied to generate different types of neurons.
It may one day contribute to defined types of neurons from patients' own stem cells.
Abstract
During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age–dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.
Authors
L. Telley, G. Agirman, J. Prados, N. Amberg, S. Fièvre1, P. Oberst, G. Bartolini, I. Vitali, C. Cadilhac, S. Hippenmeyer, L. Nguyen, A. Dayer, D. Jabaudon.
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May 10 2019 Fetal Timeline Maternal Timeline News
 dividing into daughter neural cells (in green) 5244.jpg) Progenitor cells (RED) dividing into daughter neural cells (GREEN). © UNIGE - Laboratoire Jabaudon. CREDIT © UNIGE - Laboratoire Jabaudon.
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