Gene found to play prominent role in central nervous system foundation and function
Researchers at the MRC Harwell Institute have gained new insights into the function of the gene Katnal1. Katnal1 is one of a small family of genes that have been linked with intellectual disability, autism and schizophrenia in humans. In mice, loss of function of the gene leads to poor learning and memory while the growth, migration and shape of neurons in the brain are all disturbed. This research highlights Katnal1 as a prime candidate for further study of the mechanisms underlying diseases of cognitive dysfunction.
We have approximately one billion nerve cells in our brain. These neurons form a complex architecture of networks, which communicate with each other and with other areas of the body through chemical signals. Very early in development, neurons migrate from their birthplace to their final destination in the brain. During this period they develop and form numerous elaborate branches enabling crucial connections to be made with many other neurons. Defects in these processes have been associated with many cognitive disorders.
The gene Katnal1 codes for a protein which determines the shape of microtubule structures within cells. In neurons, microtubules are important for directing neuronal migration and branching. Katnal1 and its family of genes enable the reshaping of microtubule structures at the appropriate time in developing neurons and the termination of branch growth so new ones can be formed.
This gene previously has not been well characterised, although in a small patient study loss of the gene was related to intellectual disability while one rare gene alteration has been linked to schizophrenia.
In this study, mice with a coding sequence error in Katnal1 were identified as part of a large scale genetic study. The error, or mutation, resulted in a non-functional gene – it was essentially ‘switched off’. When the behaviour of the (mutant) mice was compared to normal mice (with the correct gene) a range of behavioural abnormalities were seen including poor learning and memory.
Changes in the brain, detectable only at a microscopic level, seemed to underlie these behavioural disturbances. Analysis of different brain sections showed that the patterns of neurons in the hippocampus (a region of the brain associated with memory) and cortex (the outermost layer of the brain) were different in mutants. The cortex has well defined cell layers so anomalies are easy to spot. More neurons were seen in the outer layers of the cortex in mutants, suggesting that the neurons may have migrated too far.
Furthermore the neurons from mutants had a different shape and fewer synaptic spines – these are the structures on neurons that enable communication with other neurons.
Defects were also seen in the cilia of the mutant mice. Cilia are hair-like protrusions that stick out from all cells and are vital in early development. In the brain cilia are thought to maintain the circulation of chemicals and nutrients in the cerebrospinal fluid – a colourless fluid which maintains a healthy environment for the brain and its neurons. Defective cilia have been linked to many brain disorders including intellectual disability.
Dr Pat Nolan, one of the authors on the paper, commented:
“Our findings highlight the importance of this small group of genes in establishing the neuronal connections that are critical for precise brain functions”.
Further study of this gene and its role in neuron growth and development may provide insight into the cognitive dysfunction underlying intellectual disability and conditions such as autism. This will increase the likelihood of being able to identify therapeutic targets and potential treatments in the future.
To read the research in Molecular Psychiatry click here
Images show neurons in normal mice (left) and mutant mice (right). In the mutant mice it can be seen that the neuron branches are shorter and thinner.
CRISPR/Cas9 Quality Control
Joffrey Mianné and colleagues at the MRC Harwell Institute have published new research in Elsevier Methods outlining their proposed protocols for effectively screening the results of CRISPR/Cas9 gene editing technology.
CRISPR/Cas9 is a new gene editing technology that has revolutionised research in the field. The technology allows for faster, cheaper, and more precise gene editing than was previously possible. It is increasingly used in the field of mouse genetics to help study the relationship between genes and human disease. It is now the chosen method for the International Mouse Phenotyping Consortium (IMPC), a global project to identify the function of every gene in the mouse genome.
Despite the acceleration of the technology – the results obtained with CRISPR/Cas9 can often be unpredictable. Frequently the genetic change made is not present uniformly throughout the organism (known as mosaicism) and other unwanted changes can be found at the site where the gene has been altered. It is essential that mice taken forwards carry only the desired change so that any physiological changes seen are because of that and not something else on the genome. The ability to correctly select mice with the desired mutation requires robust and accurate methods.
The technology allows many types of genetic changes to be made, including deletions and even swapping the individual molecules making up the code of the DNA. Here the researchers have proposed a framework to analyse the results of CRISPR/Cas9 activity according to the type of genetic alteration intended. They have ascertained that due to the high level of unpredictability in the first generation it is better to definitively characterise the following generation and establish the mutant mouse line from there.
This research will contribute to the current debate on best practice for the use of CRISPR/Cas9 in biomedical research.
How CRISPR/Cas9 works
The CRISPR-Cas9 system is made up of two key molecules – the enzyme Cas9 and a piece of guide RNA. In brief, the guide RNA locates and binds to the target DNA where the change is going to be made. Its sequence is complementary to that of the target DNA. The Cas9 then acts as molecular scissors and makes a cut across both strands of DNA in the double helix. The cell then recognises that the DNA is damaged and attempts to repair it. Scientists have been able to harness the cell’s own DNA repair machinery to introduce changes into the genome.
PhD opportunities in 2017
There are four vacancies available at the MRC Harwell Institute for 4 year MRC funded PhD/DPhil Studentships starting in October 2017.
The MRC Harwell Institute is an International Centre for Mouse Genetics at the forefront of studies in mouse functional genomics and mouse models of human disease. We are engaged in lifetime studies – from developmental abnormalities through to diseases of ageing.
There are several research themes offering PhD projects at the MRC Harwell Institute for 2017:
- Genetic basis of type 2 diabetes
- Genetics of circadian rhythms and sleep in health and disease
- The genetics and pathology of deafness
- The role of cilia in development and disease
- Disorders of sex development
- Bioinformatics of mouse models of disease
- Statistical genomics
- Investigating Novel Stress Response Pathways in Neurological Disease
- Novel and bespoke mouse models for dissecting neurodegenerative disease
Click here for more information and details about how to apply.
Closing date Tuesday 7th February.
Royal Society hosts tribute to Mary Lyon
In tribute to the eminent geneticist Mary Lyon and her role in developing the theory of X chromosome inactivation, a process implicated in disease inheritance, 100 researchers from nine countries attended a scientific meeting hosted by the Royal Society. As part of the event researchers attended a one day meeting at the MRC Harwell Institute where Mary developed her theory. The event brought together worldwide experts in this dynamic field to discuss the latest research advances and reflect on the life and work of Mary Lyon, who first proposed the theory of X chromosome inactivation 55 years ago.
The meeting marked the opening of a brand new Mary Lyon exhibition at Harwell. The exhibition includes a timeline of Mary’s life surrounded by panels exploring her education, career at Harwell, and major discoveries. A map of the world pinpoints the many places she visited during her career, bringing to life her global network of researchers.
Mary’s career at Harwell spanned a period of more than 50 years and it was during this time that she made many remarkable discoveries. Mary developed the theory of X chromosome inactivation in 1961 while studying mice with different coloured patches of fur. She hypothesised that one of the two X chromosomes in the cells of female mammals is randomly inactivated during early development so that females don’t have twice the number of X chromosome gene products as males, a potentially toxic double dose. Her hypothesis, now accepted and supported by subsequent research, has had profound implications in understanding the genetic basis of X-linked diseases as well as being one of the first descriptions of epigenetic phenomena.
Mary went to Cambridge in the early 1940s, at a time when women were not official members of the university. Despite taking the same courses as men women were awarded a ‘titular’ degree. In 1998 Mary and other women from her era were officially awarded a full undergraduate degree. WW2 served to change the position of women in the world and had a strong influence on Mary’s career. Much of her research involved looking at the effects of radiation in mice as result of the events of WWII. Most of the important discoveries Mary made were offshoots of studying radiation induced mutations in mice.
Speaking at the event Dr Sohaila Rastan, one of Mary’s PhD students commented: “Now 55 years after the hypothesis was first described, Mary Lyon would have found it very gratifying to see how much research it has spawned. Although the X inactivation field has advanced so significantly some basic questions still remain unanswered.”
Professor Steve Brown, Director of the MRC Harwell Institute, said: “Mary would have relished the cut and thrust of the scientific discussion at the meeting, and would have joined in the excitement of the many new developments that were reported. She laid the groundwork for all that has followed, and the meeting was a fitting tribute to her scientific legacy.”