Publication highlights

Several models of cell fate lineages have been presented, some proposing a traditional straight path and others a more dynamic model, where cell fate remains more flexible. Researchers at the Crick combined a range of experimental techniques - single cell transcriptomics, quantitative live cell imaging and mathematical modelling - to track cell fate and determine which path is the right one. They found that there was no singular path, and these theories were not competing explanations but complementary snapshots of human development. The team also observed the influence of two important signalling molecules, Activin and BMP4, in determining which route cells would take between mesoderm or endoderm layers.

Cells need to be made in the right place at the right time in developing tissue, but how these two cues are coordinated to control cell identify is not well understood. Using mouse stem cell models of the neural tube, researchers at the Crick found a surprising "master clock" mechanism that modifies the chromatin of neural cells, making different DNA regions accessible at specific times during development. Working with the High Throughput Screening team, they identified key molecular regulators, including a transcription factor called Nr6a1, that control the temporal programme by altering chromatin accessibility. Disrupting these factors altered the identity of cells before and after becoming specialised. The ability of temporal factors in the mice to control chromatin accessibility over time explains how the same spatial progenitor domains can produce different cell types as development progresses. Taking into account the cell’s temporal clock could help engineer the generation of specific neurons and glial cells from stem cells for regenerative medicine purposes.

Researchers at the Francis Crick Institute have developed a new stem cell model of the mature human amniotic sac, which replicates development of the tissues supporting the embryo from two to four weeks after fertilisation. The new 3D model – called a post-gastrulation amnioid (PGA) – closely resembles the human amnion and other supportive tissues after gastrulation. The team developed PGAs by culturing human embryonic stem cells in a series of steps with just two chemical signals over 48 hours, after which the cells organised themselves into the inner and outer layers of the amnion. A sac-like structure formed by day 10 in over 90% of the PGAs, which expanded in size over 90 days. The researchers showed that a transcription factor called GATA3 is necessary to kick-start amnion development and that signals from the amnion can communicate with embryonic cells to stimulate growth. Finally, they believe PGAs could also provide an alternative source of amniotic membranes for medical procedures like cornea reconstruction.

Researchers at the Francis Crick Institute have revealed insight into why embryos erase a key epigenetic mark during early development, suggesting this may have evolved to help form a placenta. The team at the Crick investigated, for the first time, epigenetic changes in embryos of a marsupial, which diverged from eutherian mammals 160 million years ago. They created a map of DNA methylation in opossum eggs, sperm and embryos, finding that levels of methylation in eggs and sperm were more similar to each other than they were in eutherians. However, unlike eutherians, opossum embryos did not undergo a full wiping event. Instead, DNA methylation was retained in the early embryo, with loss occurring much later, and DNA demethylation was largely restricted to a specific supportive tissue called the trophectoderm, which becomes the marsupial placenta. These findings show that demethylation isn’t universally required for formation of an early mammalian embryo, instead, based on their findings, the team believe that wiping may have evolved specifically for the development of the placenta.

Researchers at UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

The initiation of DNA replication occurs at tens of thousands of sites on the human genome during every S phase, but in the absence of any consensus DNA sequence, it is unclear how these sites are specified. Researchers at the University of Cambridge and the Crick identified sites with increased density during quiescence and G1 phase that overlap with DNA replication origins. The increased density derives from changes made by enzymes at these sites, and inhibition of these enzymes reversibly prevented DNA replication and cell proliferation. These findings provide a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites, and for the once-per-cell cycle control of origin activation.

Organisms grow through the division of the cells that make up our bodies. As well as growth, cell division is also essential for different types of cells to decide what cell type they will become (from different neurons in our brains to the cells that line our guts). How cells divide therefore needs to be tightly controlled both in space (so that the daughter cells after division end up in the right place) and in time (so that daughter cells make the correct choice of what to become). To make this process even more complicated, each cell type is very different in terms of shape, behaviour etc…, so cell division must adapt to the needs of each tissue, an aspect of biology we know very little about. Researchers at the Crick have found a protein called Meru (called after the Bengali word for “polar”) that can tell a cell in which direction and when to divide. Meru is located at one of the poles of a cell type called the sensory organ precursor and allows this cell to orient itself in the tissue and to time its division just right to allow both daughter cells to create the right structure.

Researchers have found that the small intestine grows in response to pregnancy in mice. This partially irreversible change may help mice support a pregnancy and prepare for a second. They found that pregnant mice had a longer small intestine from just seven days into the pregnancy. By the end of the pregnancy, around day 18, the small intestine was 18% longer, and it remained longer up to 35 days after lactation. The villi and crypts inside the small intestine also became longer and deeper at the same time, but returned to pre-pregnancy values just seven days after weaning. The researchers identified an increase in a membrane protein called SGLT3a early in pregnancy. This sodium and proton sensor was responsible for about 45% of the villi growth triggered by reproduction but wasn't necessary for entire small intestine lengthening. The team believe hormones may play a role in switching on the gene for SGLT3a.

Researchers at the Crick have uncovered which genes on the Y chromosome regulate the development of sperm and impact fertility in male mice. They generated thirteen different mouse models, each with different Y genes removed, and investigated their fertility. The team found that several Y genes were critical for reproduction, and that if these genes were removed, the mice couldn’t produce young. Some other genes had no impact when removed individually, but did lead to the production of abnormal sperm when removed together. The results suggest that many Y genes play a role in fertility and can compensate for each other if one gene is lost. This also means that some cases of infertility likely result from multiple genes being deleted at the same time.

Loss of the tumour suppressor gene CDKN2A is a common early event in development of the pre-cancerous condition Barrett's oesophagus. Around 1% of Barrett's patients go on to develop oesophageal adenocarcinoma, but rather than enhancing this progression, as would be expected, early CDKN2A loss is actually protective. Having made this striking observation, the team at the Crick and collaborators showed that the reason lies with a second tumour suppressor gene, TP53. Loss of TP53 is a key driver of transformation into oesophageal cancer, but if CDKN2A is also missing, the Barrett's cells are too weakened to progress. CDKN2A changes sides to become a villain later in the process: if it's lost after the cancer has developed, it promotes a more aggressive tumour.