Summary: Researchers have identified a gene that plays a vital role in the production of neurons and glial cells in the brain.
Source: IST Austria.
Scientists at IST Austria identify Lgl1 as the gene that controls the production of neurons and glia cells in the brain. Previously unknown functions of a neurodevelopment gene clarified.
Neurons and glia are the cells that make up our brain. In the cortex, the brain area that enables us to think, speak and be conscious, neurons and most glia are produced by a type of neural stem cell, called radial glia progenitors (RGPs). It is vital that no errors occur in this process as disruptions can lead to neurodevelopmental disorders such as microcephaly, a condition in which a baby’s head and cortex are significantly smaller than that of other babies. But how is this production of neurons and glia cells controlled?
Simon Hippenmeyer and his group at the Institute of Science and Technology Austria (IST Austria), including first author Robert Beattie, as well as colleagues at North Carolina State University and the Fred Hutchinson Cancer Research Center in USA, found that a gene called Lgl1 controls the production of certain neurons in the cortex of mouse embryos, and plays a role in the production of other types of neurons and glia after birth.
This is the result of a study published today in Neuron.
The production of neurons and glia in the developing cortex is tightly regulated. RGPs produce the majority of them. In previous studies, Hippenmeyer and colleagues have shown that the division pattern of RGPs is not random. They have demonstrated that each individual RGP produces a predefined unit of neurons and glia cells in a precisely orchestrated developmental program which ensures that the brain faithfully grows to its normal size.
In the present Neuron study, the authors asked what mechanisms control the exact output of RGPs. In particular, the researchers investigated the role of the gene Lgl1, which had been predicted to regulate RGP proliferation. The gene’s precise role was previously unknown and Hippenmeyer and colleagues now used a technique called MADM, short for Mosaic Analysis with Double Markers in order to decipher the function of Lgl1 in RGPs at unprecedented single cell resolution.
Using MADM, Hippenmeyer and colleagues eliminated Lgl1 either in just single RGPs, or in all RGPs. At the same time, individual cells are labelled fluorescently, so that they can be studied under the microscope. The authors show that Lgl1 controls the generation of neurons and glia cells in the developing cortex in two different ways.
First, for the generation of neurons in the early embryo the function of Lgl1 is simultaneously required in the entire population of RGPs. If Lgl1 function is absent in all RGPs, but not if absent in just individual RGP cells, dynamic community effects lead to malformation of the cortex resembling ‘Double Cortex Syndrome’, a severe human brain disorder.
Second, for the production of glia cells and neurons in the postnatal brain, Lgl1 function is ‘only’ required in the individual stem cell which is just in the process of generating a neuron or glia cell. This type of Lgl1 gene function is called cell-autonomous or intrinsic while the requirement of Lgl1 gene function in the entire community is called non-cell-autonomous. In other words, you require the entire orchestra for a symphony (generate neurons in embryonic cortex) but only an individual soloist for a solo (produce neurons or glia cells in postnatal brain).
Simon Hippenmeyer explains how this research will influence the way how the role of genes during development should be analysed in the future: “Our study emphasizes that both intrinsic gene functions and community-based environmental contributions are important for the control of radial glia progenitor cells in the cortex in particular, and for neural stem cells in general. It will thus be important in future genetic loss-of-function experiments to precisely dissect the relative contributions of cell-autonomous, intrinsic, gene functions and the influence of the stem cell niche microenvironment to the overall interpretation of a gene function.”
Funding: The research was supported by the NOe Forschung & Bildung, European Union, Human Frontiers Science Program.
Source: Elisabeth Guggenberger – IST Austria
Image Source: NeuroscienceNews.com image is credited to Maria Cristina Travaglio.
Original Research: Abstract for “Mosaic Analysis with Double Markers Robert Beattie, Maria Pia Postiglione, Laura E. Burnett, Susanne Laukoter, Carmen Streicher, Florian M. Pauler, Guanxi Xiao, Olga Klezovitch, Valeri Vasioukhin, Troy H. Ghashghaei, and Simon Hippenmeyer in Neuron. Published online May 3 2017 doi:10.1016/j.neuron.2017.04.012
Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells
•MADM-based genetic dissection of intrinsic gene function and community effects
•Sparse and complete Lgl1 ablation distinctly affects RGP-mediated neurogenesis
•Lgl1 cell-autonomously controls astrocyte generation in an EGFR-dependent manner
•Critical role for Lgl1 in postnatal NSC lineage progression and neurogenesis
The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms.
“Mosaic Analysis with Double Markers Robert Beattie, Maria Pia Postiglione, Laura E. Burnett, Susanne Laukoter, Carmen Streicher, Florian M. Pauler, Guanxi Xiao, Olga Klezovitch, Valeri Vasioukhin, Troy H. Ghashghaei, and Simon Hippenmeyer in Neuron. Published online May 3 2017 doi:10.1016/j.neuron.2017.04.012