Towards a Natural Genetic Architecture of Cell Proliferation

  • Research
Published on May 16, 2023 Updated on July 4, 2023

on the May 16, 2023


A study, published in Nature Communications in May 2023 by Christian Braendle's team at the Valrose Institute of Biology, shows that complex epistatic interactions are important factors that can contribute to the natural variation of stem cell niche activity. These results provide the first views into the quantitative genetic architecture of an animal stem cell system at molecular resolution.

Stem cells are of fundamental importance for understanding the development and diseases of the body. Yet how stem cell proliferation varies between individuals and within natural populations remains unclear. A new study, published in Nature Communications by Christian Braendle's team at the Valrose Institute of Biology, shows how the natural variation in the germline stem cell system of the nematode Caenorhabditis elegans can be explained by surprisingly complex molecular interactions throughout the genome.

The regulation of cellular proliferation is a fundamental aspect of the development of an organism, often coordinated by stem cell niches. Small disturbances in the activity of stem cell niches can greatly disrupt tissue growth and maintenance and cause pathologies such as cancer. 
While genetic studies in animal species have revealed the evolutionary conservation of key molecular mechanisms regulating stem cells, how the activity of stem cell systems is modulated by the genetic diversity present in natural populations is not yet known. 

Focusing on the germline stem cell niche of the nematode Caenorhabditis elegans, the new study shows that stem cell activity exhibits high variability in natural populations. Using quantitative genetic approaches, the researchers identified multiple interacting genomic regions that explain the natural quantitative variation in stem cell niche activity. 

In particular, they discovered a natural variation in the promoter region in the Delta (lag-2) gene, an essential signal for maintaining germline stem cells via the Notch pathway, a evolutionarily conserved molecular pathway that also plays an important role in development and disease in humans. 

To investigate the effects of this natural variation in the Delta (lag-2) signal, and interactions with other genomic variants, scientists generated reciprocal allelic replacement lines in different natural strains of C. elegans using CRISPR-Cas9 technology. Contrary to expectations, the phenotypic effect of the natural variant Delta (lag-2) depended strongly on the genotype in a second genomic region, and also on the genetic background as a whole. Thus, it is not possible to predict a priori the effect of a mutation in a key gene regulating stem cells, due to epistasis phenomena, characterized by nonlinear gene-gene interactions.

Higher-order epistasis shapes natural variation in germ stem cell niche activity.
Sarah R Fausett, Asma Sandjak, Bénédicte Billard, & Christian Braendle
Nature Communications 2023, sous presse


Christian Braendle - Directeur de Recherche CNRS - +33 4 89 15 08 40 -

schema Braendle
schema Braendle © Sarah Fausett and Christian Braendle


The germline stem cell system in the nematode. The germline progenitor zone, located at the distal end of each gonad arm, contains mitotically dividing stem and progenitor cells. The germline stem cell pool is maintained through Delta/Notch signaling by the somatic distal tip cell (green), which enwraps the distal cells. The Delta ligand (LAG-2) activates the Notch receptor (GLP-1) in germ cells to maintain stem cells while also preventing meiotic entry. The germ cells differentiate into gamete progenitors through meiotic stages as they progress toward the proximal end of the gonad arm.

Traduction des mots figurant dans l’illustration:
Méiose = Meiosis
Cellules souches = Stem cells
Niche (signal Delta/Notch) = Niche (Delta/Notch signal)
Cellules souches = Stem cells
Méiose = Meiosis
Embryons = Embryos
Delta/LAG-2 = Delta/LAG-2
Notch/GLP-1 = Notch/GLP-1