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Explore a selection of research case studies from the past five years.

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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Neurons in the brain

Researchers identify new way to treat genetic epilepsy by replacing ‘lost’ enzyme

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.

Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain

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Published in Molecular Psychiatry

Published

Electrical recordings from fluorescent mammalian cells (green) which are used to study the action of CDKL5 kinase on calcium channels. Red shows the calcium channels and pink shows CDKL5 kinase.

New therapeutic target for rare type of childhood epilepsy

Researchers at the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy called CDKL5 deficiency disorder (CDD). They examined mice which lacked the Cdkl5 gene, and used a technique called phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme. They identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. This is needed for the nervous system to function properly, but too much calcium coming into cells can result in overexcitability and seizures. Mutations in Cav2.3 that enhance channel activity are already known to cause severe early onset epilepsy in a related condition called DEE69, which shares a lot of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures.

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

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Published in Nature Communications

Published

A group of neurons, glial cells and immune cells within the gut wall.

Glia in the gut shown to maintain the potential to become neurons

Innervation of the gut is necessary for the regulation of digestive functions and for protection from micro-organisms which cause disease. To perform these important tasks, the gut is colonised during embryonic development by a small population of unspecified cells that expands rapidly and generates a vast number of specialised nerve cells, that control the movement of food through the gut. This population also generates support cells called glial cells. These protect the nerves and at the same time help the rest of gut tissue to fight infections and repair potential damage caused by them.

By characterising the molecular properties of these cell populations at several developmental stages and in adult animals, researchers at the Crick uncovered rules which control the assembly of the nervous system of the gut and how its constituent cell types acquire their properties. The team also showed that the support cells of the gut nervous system preserve the ability to form new nerves throughout life. These new findings will help us understand the development of some of the most severe gastrointestinal disorders and develop novel strategies for their treatment.

A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia

Published in Nature Communications

Published

Sila Ultanir banner

New inhibitors to study a rogue brain enzyme

Mutations in the CDKL5 protein cause CDKL5 deficiency disorder (CDD), an infantile-onset, resistant epilepsy with generalised neurodevelopmental deficits. CDKL5 is a brain-enriched serine/threonine kinase with few known substrates and unknown functions in brain development. It is rather similar to a second kinase, GSK3b, which has also been linked to synaptic function, making it hard to distinguish which kinase is responsible for what effect in the brain. Sila Ultanir and collaborators have developed selective CDKL5 inhibitors that do not have detectable activity for GSK3b, providing important new tools to gain insights into the role of CDKL5 in brain health and disease.

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Published in eLife

Published

Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme

Unlike kinases, PPP-family phosphatases such as PP1 have little intrinsic specificity. PP1 acts in partnership with over 200 different PP1-interacting proteins, but it has remained unclear how they might confer sequence-specificity on PP1. We used proteomics to identify dozens of candidate Phactr1/PP1 substrates, and used structural and biochemical approaches to show that the Phactr1/PP1 holoenzyme is sequence-specific. Phactr1 binding reshapes the PP1 hydrophobic groove, thereby creating a novel composite hydrophobic surface for substrate recognition. This study explains how cofactors can enhance the reactivity of PP1 toward specific substrates, and suggests a way forward for the development of PP1 holoenzyme-specific inhibitors.

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Published in eLife

Published

YAP1/TAZ drives ependymoma-like tumour formation in mice

We showed that active YAP1 in radial glia derived neural precursor cells induces ependymoma-like tumours in mice. We demonstrated that YAP1 is necessary and sufficient using mouse models. We found that transcription coactivator HOPX, a factor consistently suppressed in malignancies, is highly expressed in our mouse models and in YAP1-fusion human ependymoma. HOPX differentiates YAP1-fusion subtype from the highly malignant RELA-fusion human ependymomas. This supports the notion for subtype-specific care for ependymoma.

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Published in Nature Communications

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.