Making cell fate decisions during development - CDB researchers and collaborators gain new insight

An adult human body is made up of trillions of cells, with at least 400 different types of cells, such as muscle cells and neurons. How such a vast diversity of cell types is achieved from what started as a single-cell embryo is truly remarkable. Biologists have been trying to understand how cells with the same DNA turn out to be so different, each with their own unique identity and function.

The answer lies in an evolutionarily conserved process called asymmetric cell division, where two daughter cells, generated from the same mother cell, acquire distinct identities. Despite having identical DNA, these daughter cells have different gene expression programs that only allow the activation of genes relevant to their identity. How different gene expression programs are established during asymmetric cell division remains a puzzle that scientists are actively trying to better understand. 

In this study published in Nature Communications, Nadin Memar and colleagues have discovered an unexpected player that influences cell fate decisions and gene expression programs during asymmetric cell division - the evolutionarily conserved CMG (Cdc45-MCM2-7-GINS) complex.

Discovering an unexpected role of CMG in cell fate decisions

The CMG complex is most well-known for acting as a “DNA unzipper”, unwinding double-stranded DNA to allow cells to replicate their genetic material in preparation for cell division. However, Nadin Memar and co-researchers found that CMG has a surprising new role: it also influences the fate of daughter cells during asymmetric cell division.

This exciting discovery was made using the nematode Caenorhabditis elegans, a nematode worm, which has served as a formidable model organism for research in the life and biomedical sciences. Nobel prize-winning work done by Brenner, Horvitz and Sulston almost 50 years ago meticulously mapped the cell division and cell fate patterns of these microscopic worms, creating a powerful tool for researchers to reproducibly track specific cells and their fates.

Using this tool to their advantage, the authors focused on asymmetrically dividing mother cells, where one daughter cell dies (‘cell death’ fate) while the other daughter cell survives (‘cell survival’ fate) (as shown in the diagram). This presented them with an excellent paradigm to explore how cell fate decisions (death versus survival) are made during asymmetric cell division.

Using a clever unbiased genetic screen, they made a remarkable discovery - when they reduced the function of CMG, the dying daughter cells wrongly acquired the fates of their sister cells and instead survived (see diagram). Furthermore, the team showed that CMG’s unexpected role is not restricted to ‘death or survival’ decisions, but also extends to other cell fate decisions such as becoming a neuron or a non-neuronal cell such as a glial cell. This finding showed that CMG has a more general role in influencing cell fate decisions during C. elegans development.

Identifying the target of CMG in death versus survival decisions

Further experiments revealed that, in the context of death or survival decisions, CMG promotes the differential expression of egl-1, a gene essential for cells to die. Normally, egl-1 expression is activated in daughter cells ‘programmed’ to die and repressed in the surviving sister cells (see diagram). However, they found that, when the function of CMG is reduced, the expression of egl-1 in cells programmed to die is lost, leading to incorrect survival of these cells. These findings not only highlighted a role of CMG in promoting the death or survival decision, but also identified it as a key regulator of egl-1 expression.

Memar and collaborators also found that egl-1 is expressed at low levels in the mother cell, and its expression is subsequently retained in the dying daughter cell (see diagram). This phenomenon, known as multilineage priming, occurs when a gene is activated in the mother cell and its expression is retained only in one of the daughter cells. The mechanisms behind multilineage priming are poorly understood, and this study for the first time implicates CMG in this process.

Providing the first in vivo evidence for this new role of CMG in cell fate decisions

In addition to replicating the genetic material, dividing cells must also package the newly made DNA with the help of proteins so that it can fit into the nucleus. This compact structure made of DNA and proteins is called chromatin, which forms the chromosomes in the nucleus of eukaryotic cells. In fact, chromatin does not only help fit the DNA into the nucleus, but it also carries information that plays a crucial role in regulating gene expression.

Interestingly, recent studies performed in yeast and mammalian cells grown in culture dishes have shown that CMG helps to maintain the information carried by chromatin during cell division. Importantly, this role of CMG is required for mouse embryonic stem cells to acquire a cell fate, such as the neuronal fate. However, this new role of CMG had not yet been confirmed in cells within a living organism (in vivo).

Therefore, the findings from this study, published in Nature Communications, are very exciting. They provide the first key evidence for CMG’s role in regulating cell fate decisions and gene expression programs in a developing animal.

The authors also propose that CMG’s unexpected role in death or survival decisions in C. elegans may be linked to CMG’s ability to package DNA at the egl-1 gene during cell division. However, further studies are required to test this idea, which the team led by Barbara Conradt is actively pursuing. 

The study could illuminate disease mechanisms and provide potential therapeutic targets

The discoveries made by this study offer new insights into how different cell types are generated during animal development. Many conditions, including autoimmunity, cancer and developmental abnormalities, arise from muddling of cell identities during development. By better understanding mechanisms enabling cell fate decisions, their study could pave the way for new strategies into potential solutions for such conditions in the future.

[Reference information: Nadin Memar ^1 2, Ryan Sherrard ^# 3, Aditya Sethi ^# 4, Carla Lloret Fernandez ^# 4, Henning Schmidt ⁵, Eric J Lambie ⁴, Richard J Poole ⁴, Ralf Schnabel ⁵, Barbara Conradt ⁶ The replicative helicase CMG is required for the divergence of cell fates during asymmetric cell division in vivo. Nat Commun. 2024 Oct 30;15(1):9399. PMID: 39477966. PMCID: PMC11525967.  DOI: 10.1038/s41467-024-53715-2]