Nervous system discovery overturns previous theory

**Discovery concerning the nervous system overturns a previous theory
Fig. 1 From: A cell fitness selection model for neuronal survival during development Differential expression of TRKC in PSNs prior to the cell death period. a Scheme of our working hypothesis. b, c Temporal fate mapping of TRKC PSNs by 4-OHT induction. TrkCCreER mice allow temporary activation of CreER in the TRKC+ cells 2 h after 4-OHT injection21,22. Immunostaining for PV, RFP and RUNX3 on E17.5 DRG sections (c) and graph showing distribution of PV+/RUNX3+ PSNs among the TOM+ cells (n = 4). Scale bar: 20 μm. d Quantification of PSNs at C5 and C7. ***P < 0.001, one-way analysis of variance (ANOVA) with Sidak’s multiple comparisons test (n = 2–3). The window of PSNs cell death is shown. e TRKC expression in E11.5 ISL1+ (and RUNX3+, whose staining is not shown for more visibility) DRG neurons. Scale bar: 50 μm. f TRKC levels in PSNs of e illustrated by color coding; dark blue indicates the lower and red the higher TRKC levels. From here, all observations are done at brachial levels (C5–8). g Distribution of TRKC levels in PSNs from e. h Distribution of TRKC levels in PSNs in E11.5 DRG neurons (from g). The data exhibit a Poisson-like distribution (one representative animal), with the mean used to define the two different categories of TRKC intensity (TRKCHigh and TRKCLow). i Projection of seven images of RUNX3+/TRKC+ PSNs from one brachial DRG; dots indicate TRKC-labeled neurons and color codes reveal TRKC intensity as shown in h. j Projection image of smFISH for pan Ntrk3 and Ntrk3 full length (FL) transcripts in E11.5 DRG, visualized at high magnification in (1) and (2) (images show full projection); right panel shows color coding of Ntrk3 FL levels in red; the brighter, the higher levels. k Distribution of the number of Ntrk3 FL molecules in E11.5 DRG neurons by smFISH, normalized to pan Ntrk3 (Ntrk3 FL represent 68% of all Ntrk3 transcripts). l TrkCCreER;R26tdTOM mice were injected at E9.75 with 4-OHT and analyzed at E11.5 (n = 3). m, n Frequency distribution (m) and pie chart (n) of TOM+/TRKC+ neurons from l according to their level of TRKC intensity. Source data are available as a Source Data file

It appears that when the nervous system is developing, only the most viable neurons survive, while immature neurons are weeded out and die. This is shown in a groundbreaking discovery by researchers at Karolinska Institutet in Sweden. The results indicate that the longstanding neurotrophic theory, which states that chance determines which cells will form the nervous system, needs to be revised.

During the early stages of the development of the , an excess of is generated. At a certain time, a large portion of these then die, which is a necessary step for the proper formation of the nervous system. The process takes about 24 hours, and in certain parts of the nervous system, roughly half of all neurons disappear.

Researchers have previously believed this to be a in which all cells have an equal chance of survival. However, researchers from Karolinska Institute have now publishing a study in Nature Communications showing that cell death instead appears to be controlled by a mechanism that weeds out the less fit cells.

"The cells that survive are more mature and inclined to form synapses with other ," says Saida Hadjab, who coordinated the study together with Francois Lallemend. They are both researchers at the Department of Neuroscience at Karolinska Institutet.

Several years ago, Hadjab and Lallemend noted that the early neurons are different. On their surfaces are receivers of growth factors that stimulate their survival. Hadjab and Lallemend discovered that certain neurons have more of these receivers than others. They started to suspect that cell death is somehow controlled such that only certain selected cells survive.

The researchers have now conducted a detailed study of individual neurons in the early nervous system in mice, and among other things, have discovered which genes are active. Their mapping revealed two distinct molecular patterns that determine the fate of these cells. The cells that are the most capable of growing and forming connections to other neurons survive, while the more immature cells die.

The study was performed in the peripheral sensory nervous system. Whether is controlled in the same way in other parts of the nervous system remains to be discovered.

"This discovery can help us understand the brain and the development of the nervous system on a different level. Earlier studies have mainly studied the environment surrounding the cell, and neuronal population as homogenous cell type. Researchers have not examined the actual neurons individually, their fitness and how different they are," says Francois Lallemend.

This discovery could potentially be significant to the treatment of different neurological diseases. For example, in the case of Parkinson's disease, doctors have tried to transplant healthy stem cells in patients, but the majority of cells die shortly after the treatment. It is possible that the treatment could become more successful if the less fit cells were weeded out before the transplant so that the patient was only given viable neurons.


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More information: "A cell fitness selection model for neuronal survival during development", Yiqiao Wang, et al Nature Communications, September 12, 2019, DOI: 10.1038/s41467-019-12119-3. https://www.nature.com/articles/s41467-019-12119-3
Journal information: Nature Communications

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