Publication highlights

Scientists at the Crick and Barts Cancer Institute (Queen Mary University of London) have discovered that a single letter change in the PRKCA gene drives a rare and hard-to-treat brain cancer, chordoid glioma. The PRKCA gene contains instructions for making a protein called protein kinase C alpha (PKCa). Until now, many believed blocking kinases would be useful for treating cancer, but in this study the team discovered that the mutation in PRKCA blocks the kinase but paradoxically drives tumour growth. This was because it became locked in a shape that allowed it to promote cancer cell growth signalling and because it interacted with epigenetic regulators in a way that promoted cancer growth.

Cryopreservation methods for archiving and distributing mouse strains mostly focus on freezing embryos or sperm. In contrast, the cryopreservation of oocytes (eggs) is not widely adopted in large biomedical research facilities, due to highly variable results and challenges in validating methods to preserve genetically modified oocytes on a large scale. The Genetic Modification Service at the Crick has developed a robust vitrification protocol for large-scale oocyte cryopreservation, achieving high viability and fertilisation rates comparable to fresh oocytes. They have extensively tested the protocol for in vitro fertilisation of 13 genetically altered strains, using both genetically altered and wild-type oocytes and sperm. Combining these genetically modified cryopreserved oocytes with an archive of cryopreserved sperm allows the generation of embryos with different genetic combinations. This potentially reduces subsequent breeding steps and the need to maintain live stocks of certain mouse strains.

Researchers at the Crick and Australian National University have shown how two proteins, TCF1 and LEF1, previously only studied in T cells, enable B-1 cells (a type of innate B cell which remains uncharacterised in humans) to apply the brakes on inflammation in mice and used this information to identify signs of B-1 activity in humans. They found that removing TCF1 and LEF1 in adult mice led to the production of a smaller number of dysfunctional B-1a cells that failed to restrain an immune assault on the brain resembling multiple sclerosis. Cells without TCF1 and LEF1 also produced significantly less of an anti-inflammatory compound, IL-10. Finally, the team analysed pleural fluid from people with pleural infections, finding an abundance of B-1-like cells which expressed both genes, as did malignant B cells in people with chronic lymphocytic leukaemia. They also conclude that TCF1 and LEF1 could be harnessed to increase the effectiveness of other immune cells.

Researchers at the Francis Crick Institute have shown that gonadotrophs, cells in the pituitary gland with a key role in puberty and reproduction, come from two different populations, with the majority produced after birth rather than in the embryo, as previously thought. The team genetically marked and traced the descendants of a population of stem cells in the mouse pituitary gland, as they developed into different types. By following the markers from birth up to one year, the team saw that the stem cell pool almost exclusively became gonadotrophs rather than other types of pituitary cells. This process started after birth and continued until puberty in what is known as the ‘minipuberty’ period in mice. They also showed that the two populations are located in separate compartments in the pituitary gland. This work highlights a window of opportunity in early life to diagnose disorders causing absent or delayed puberty.

Researchers at the Crick have developed tools for efficient integration and robust expression of transgenes in mouse and human stem cells. Three different integrase enzymes were compared in mouse embryonic stem cells and the most efficient enzyme, called Bxb1, was adapted for use in human induced pluripotent stem cells. The technique was used to equip these human stem cells with CRISPR machinery, allowing genes to be up or down regulated by introducing a single RNA guide molecule into the human stem cells. These approaches can be used to identify genes of interest in stem cells.

Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy, by studying mice that don’t make the CDKL5 enzyme. The team measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn’t produced. Even in mice that don’t produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons, suggesting that increasing the level of CDKL2 in people deficient in CDKL5 could potentially treat some of effects on the brain in early development.

Researchers from the Reis e Sousa lab have identified a protein that helps tumours evade the immune system and, in certain types of cancers, is linked to a poorer chance of survival. The protein could become a target for future cancer treatments.