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Developmental Biology - Brain Development

Why Half of All Neurons Die

The long-standing theory of neurons, which states chance determines which cells will form the nervous system, needs to be revised...

It appears that when the mouse embryonic nervous system is developing, only the most viable neurons survive while immature neurons are weeded out to die. This ground-breaking discovery from researchers at Karolinska Institutet in Sweden indicates the long-standing theory that "chance determines which cells will form the nervous system" is wrong.
This discovery can help us understand the brain and the development of the nervous system on a different level. Earlier research studied the environment surrounding a cell and neuronal population of homogenous cell types, but did not examine actual neurons individually for fitness or for how different they are from each other."

Francois Lallemend PhD, Department of Neuroscience and the Ming Wai Lau Centre for Reparative Medicine, Stockholm, Karolinska Institutet, Stockholm, Sweden.

The current research is significant in that different neurological diseases may potentially be more successfully treated with transplanted cells. For example, Parkinson's Disease doctors have tried to transplant healthy stem cells in patients, but the majority of new cells die shortly after transplant. Possibly, by introducing cells where less fit cells are eliminated beforehand, cell transplants will become more successful.

During early stages of embryo development when the nervous system is being generated, an excess of neurons are made. Within 24 hours of beginning to differentiate, a large portion of these cells then die. This appears to be a necessary step for the proper formation of the nervous system, with roughly half of all neurons disappearing.

Researchers believed this was a random process, where all cells had an equal chance of survival. However, the published study in Nature Communications shows that cell death instead appears to be controlled by a mechanism for weeding out less fit cells.
"The cells that survive are more mature and inclined to form synapses with other nerve cells"

Saida Hadjab PhD, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; coordinator of the study with Francois Lallemend.

Several years ago, Saida Hadjab and Francois Lallemend noted how early neurons were different. Their cell surfaces were studded with "receivers" for growth factors which stimulate their survival. Hadjab and Lallemend observed certain neurons had more "receivers" than others and both researchers began to suspect cell death was somehow affected, with only certain select cells surviving.

The team's detailed study of individual neurons in the early nervous system of mice reveals which genes are trully active. Their gene mapping has revealed two distinct molecular patterns determine the fate of these neuronal cells. The cells that are the most capable of growing and forming connections to other neurons survive, while the more immature cells die.

Their study was performed in the peripheral sensory nervous system. Whether cell death is controlled in the same way in other parts of the nervous system remains to be explored.

Developmental cell death plays an important role in the construction of functional neural circuits. In vertebrates, the canonical view proposes a selection of the surviving neurons through stochastic competition for target-derived neurotrophic signals, implying an equal potential for neurons to compete. Here we show an alternative cell fitness selection of neurons that is defined by a specific neuronal heterogeneity code. Proprioceptive sensory neurons that will undergo cell death and those that will survive exhibit different molecular signatures that are regulated by retinoic acid and transcription factors, and are independent of the target and neurotrophins. These molecular features are genetically encoded, representing two distinct subgroups of neurons with contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neurons provides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrate into neural networks.

Yiqiao Wang, Haohao Wu, Paula Fontanet, Simone Codeluppi, Natalia Akkuratova, Charles Petitpré, Yongtao Xue-Franzén, Karen Niederreither, Anil Sharma, Fabio Da Silva, Glenda Comai, Gulistan Agirman, Domenico Palumberi, Sten Linnarsson, Igor Adameyko, Aziz Moqrich, Andreas Schedl, Gioele La Manno, Saida Hadjab and François Lallemend.

The authors thank D. Ginty for the TrkCCreER mice; Y. Groner and D. Levanon for the Runx3 mice; C. Ibanez for the R26tdTOM mice; P. Ernfors, H. Abdo and L. Calvo Henrique for the R26CreERT2;R26tdTOM mice; T. Jessell for the RUNX3 antibody; N. Ghyselinck and P. Dollé (IGBMC, Strasbourg) for the Raldh floxed mice; the CLICK imaging Facility supported by the Knut and Alice Wallenberg Foundation. We are also grateful to Prof. A. El Manira and P. Ernfors for critical reading of the manuscript. This work was supported by the Swedish Research Council (VR), the Ragnar Söderberg Foundation, Knut and Alice Wallenberg Foundation, Swedish Brain Foundation, Karolinska Institutet, the Karolinska Institutet Strategic Research program in Neuroscience (StratNeuro), the Ming Wai Lau Foundation and Åke Wiberg Foundation (F.L.); by RARENET V No. 1.7 EU Regional Development Fund, University of Strasbourg Institute of Advanced Studies (USIAS) (K.N.); and by ERC (BRAINCELL grant 261063), VR, the Wellcome Trust (grant 108726/Z/15/Z), and the EU (FP7/DDPDGENES) (S.L.). F.L. is a Ragnar Söderberg fellow in Medicine, a Wallenberg Academy Fellow in Medicine and a MWLC investigator.

The study has been carried out in collaboration with other researchers at the Karolinska Institute, as well as researchers at the University of Strasbourg, the University of Côte d'Azur, the Pasteur Institute, the Medical University in Vienna, IBDM in Marseille and EPFL in Lausanne. The study was funded by contributions from the Karolinska Institute, the Swedish Research Council, the Knut and Alice Wallenberg foundation, StratNeuro, the Ragnar Söderberg foundation, the Ming Wai Lau Center and the European Research Council.

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Sep 13 2019   Fetal Timeline   Maternal Timeline   News  

One of 1,000s of statistical mouse brain regional profiles. Blue/red nodes represent either hemisphere
of the mouse brain. Neuronal patterns are regulated by retinoic acid and transcription factors,
and are also genetically encoded for a higher capacity to survive.
CREDIT Karolinska Institutet, Sweden.

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