Neurons and glia are the cells that make up our human brain. In the cortex, the brain area that enables us to think, talk and be conscious, neurons and most glia are produced by a kind of neural stem cell, called radial glia progenitors (RGPs). It is vital that no errors occur in this process because disruptions can lead to neurodevelopmental disorders such as microcephaly, a condition where a baby’s head and cortex are significantly smaller compared to that of other babies. But how is this production associated with neurons and glia cells controlled? Simon Hippenmeyer great group at the Institute of Science and Technology Luxembourg (IST Austria), including first author Robert Beattie, in addition to 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 within the cortex of mouse embryos, and plays a role in the production associated with other types of neurons and glia after birth. This is actually the result of a study published today in Neuron .
The production of neurons and glia in the developing cortex is tightly controlled. RGPs produce the majority of them. In previous studies, Hippenmeyer plus colleagues have shown that the division pattern of RGPs is just not random. They have demonstrated that each individual RGP produces the predefined unit of neurons and glia cells in the precisely orchestrated developmental program which ensures that the brain consistently grows to its normal size.
In our Neuron study, the writers 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 particular gene’s precise role was previously unknown and Hippenmeyer plus colleagues now used a technique called MADM, short just for Mosaic Analysis with Double Markers in order to decipher the particular function of Lgl1 in RGPs at unprecedented solitary cell resolution.
Using MADM, Hippenmeyer plus colleagues eliminated Lgl1 either in just single RGPs, or even 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 will Lgl1 controls the generation of neurons and glia cells in the developing cortex in two different ways. Initial, for the generation of neurons in the early embryo the particular function of Lgl1 is simultaneously required in the whole population of RGPs. If Lgl1 function is missing 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 condition. Second, for the production of glia cells and neurons in the postnatal brain, Lgl1 function is ‘only’ needed in the individual stem cell which is just in the process create 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. To put it differently, you require the entire orchestra for a symphony (generate neurons within embryonic cortex) but only an individual soloist for a solitary (produce neurons or glia cells in postnatal brain). Simon Hippenmeyer explains how this research will impact the way how the role of genes during development must be analysed in the future: “Our study emphasizes that both inbuilt gene functions and community-based environmental contributions are important for your control of radial glia progenitor cells in the cortex especially, and for neural stem cells in general. It will thus make a difference in future genetic loss-of-function experiments to precisely dissect the relative contributions of cell-autonomous, intrinsic, gene features and the influence of the stem cell niche microenvironment towards the overall interpretation of a gene function. ”
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