Study Uncovers 198 Genes Associated With Brain Morphogenesis in Mice

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By IMPC

Published 4th October 2019

With a contribution from the IMPC, recent research, published in Nature Communications, has identified 198 genes associated with brain morphogenesis in mice – 83% of these constitute genes newly implicated in brain architecture.

Brain development and morphogenesis is critical to higher-order cognition, but our knowledge of its biological basis is at best incomplete, and at worst, severely lacking. Previous studies have demonstrated that there is a significant genetic influence on brain morphology. However knowledge of which genes influence brain morphology is limited, and this presents an important problem in developmental biology. By identifying 198 genes that are associated with mouse brain morphogenesis the study provides a complementary resource to human genetic studies and predicts that many more genes could be involved in mammalian brain morphogenesis.

Binnaz Yalcin, corresponding author of the study says “This study aims at understanding the genetics of brain anatomy in the mouse. It provides a wealth of novel knowledge about which genes control the size and the shape of the brain, and a foundation on which neurobiologists can build to further study how exactly these genes control the brain anatomy”.

“I have no doubt that this resource will help medical geneticists working on ultra-rare human neurodevelopmental disorders

The researchers obtained brain samples of 1566 mutant mouse lines from the Sanger Institute Mouse Genetics Project, a partner of the IMPC. Using a histological pipeline, 118 brain morphological parameters were analysed, covering brain size, commissures, ventricles, cortex, subcortex and cerebellum. To detect neuroanatomical phenotypes (NAPs), the researchers used PhenStat, a statistical method developed by the IMPC for the identification of abnormal phenotypes. 198 genes associated with neuroanatomical phenotypes (NAP genes) were subsequently identified. The vast majority of these genes (94%) have never previously been associated with brain anatomy in mice.

Interestingly, unique human orthologs were identified for 173 of the identified mouse NAP genes. Whilst 17% of human unique orthologs of mouse NAP genes are known loci for cognitive dysfunction, 83% constitute a vast number of genes that are newly implicated in brain architecture. This dataset may therefore help in improving clinical interpretation.

Yalcin states “I have no doubt that this resource will help medical geneticists working on ultra-rare human neurodevelopmental disorders who sometimes struggle to determine the genetic mutation responsible for the underlying disease, when for example there is only one patient world-wide. So when a mutation is found in a patient’s genome and that patient exhibits the same phenotype than the mouse, a molecular diagnosis can finally be made.”

This study would not have been possible without the IMPC

The identified NAP genes converge into a small number of groups of functionally similar genes participating in shared cellular pathways. Disruption of genes within the same module can yield a similar pattern of neuroanatomical abnormalities, revealing interesting neurodevelopmental pathway/phenotype relationships. For example, the study indicates that mechanisms confined to sub-cellular compartments as subtle as dendritic spines can translate into major anatomical features.

The study represents the largest atlas of the link between genetic mutation and its associated neuroanatomical features yet, and contributes a wealth of new knowledge on the genetics of brain morphogenesis. The authors were keen to note the contribution of the IMPC towards their work, with Yalcin commenting that “This study would not have been possible without the IMPC and is a tribute to the remarkable work of the people involved in this consortium.”

The IMPC is aiming to design and produce a genome-wide mouse strain resource of human disease-associated coding variants associated with rare disease that can be used for validation of putative functional variants and insight into disease mechanism(s). To find out more, click here.


Original publication: Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis

We are excited to be attending the the SfN 2018 Annual Meeting in San Diego starting this weekend. We are looking forward to engaging with researchers and to raising awareness of the IMPC as a resource. If you are attending the conference and want to learn more about the IMPC please visit stand 4132.

We will be tweeting relevant research and news during the conference so please follow us on Twitter for updates. We are also adding guest blog posts from attendees presenting research that utilize mouse models. As well as documentation and information about our latest research, we will also be giving out coasters, pens, notebooks and toy mice. Please don’t hesitate to come to our stand if you are interested in hearing more about the IMPC!

What is the International Mouse Phenotyping Consortium?

The International Mouse Phenotyping Consortium (IMPC) is an international effort to identify the function of every gene in the mouse genome. The entire genome of many species has now been published and whole genome sequencing is becoming relatively quick and cheap to complete. Despite these advancements the function of the majority of genes remains unknown.

This is where the IMPC comes in, with the goal of phenotyping all 20,000 or so protein coding mouse genes. To achieve this, genes in the mouse genome are switched off then standardised physiological tests undertaken across a range of biological systems. This data is then made freely available to the research community. As well as completing large scale comparative studies, the overall aim of the project is to create a platform for this data where researchers/clinicians can search for genes or diseases of interest to help them understand human health and disease.

IMPC data can be used in a variety of ways, such as to investigate basic biology mechanisms that can lead to new therapeutic targets or to narrow down a suspected list of genes in patients. In the last few years the IMPC have made major discoveries in parts of the genome that were hitherto unexplored, with new genes discovered relating to areas such as deafness, diabetes, and rare diseases. Summaries of five recent research articles that highlight the diversity of how IMPC data can be used are listed below.

More information on the objectives and background of the IMPC can be found on our main website: https://www.mousephenotype.org/objectives-and-background

A new study published in the journal Neuron sheds light on the normal function of LRRK2, the most common genetic cause for late-onset Parkinson’s disease. The knockout alleles for this research were acquired from the KOMP Repository.

For more than 10 years, scientists have known that mutations in the LRRK2 gene can lead to Parkinson’s disease, yet both its role in the disease and its normal function in the brain remain unclear. In a study in mice, researchers have now found that LRRK is necessary for the survival of dopamine-containing neurons in the brain, the cells most affected by Parkinson’s. Importantly, this finding could alter the design of treatments against the disease.

“Since its discovery, researchers have been trying to define LRRK2 function and how mutations may lead to Parkinson’s disease,” said Beth-Anne Sieber, Ph.D., program director at NINDS. “The findings in this paper emphasize the importance of understanding the normal role for genes associated with neurodegenerative disorders.”

LRRK2 is found along with a closely related protein, LRRK1, in the brain. A mutation in LRRK2 alone can eventually produce Parkinson’s disease symptoms and brain pathology in humans as they age. In mice, however, LRRK2 loss or mutation does not lead to the death of dopamine-producing neurons, possibly because LRRK1 plays a complementary or compensatory role during the relatively short, two-year mouse lifespan.

“Parkinson’s-linked mutations such as LRRK2 have subtle effects that do not produce symptoms until late in life. Understanding the normal function of these types of genes will help us figure out what has gone wrong to cause disease,” said Jie Shen, Ph.D., director of the NINDS Morris K. Udall Center of Excellence for Parkinson’s Disease at Brigham and Women’s Hospital and senior author of this study.

To better understand the roles of these related proteins in brain function using animal models, Shen and her colleagues created mice lacking both LRRK1 and LRRK2. They observed a loss of dopamine-containing neurons in areas of the brain consistent with PD beginning around 15 months of age. When the researchers looked at the affected brain cells more closely, they saw the buildup of a protein called α-synuclein, a hallmark of Parkinson’s, and defects in pathways that clear cellular “garbage.” At the same time, more dopamine-containing neurons also began to show signs of apoptosis, the cells’ “self-destruct” mechanism.

“Our findings show that LRRK is critical for the survival of the populations of neurons affected by Parkinson’s disease,” said Dr. Shen.

While the deletion of both LRRK1 and LRRK2 did not affect overall brain size or cells in such areas of the brain as the cerebral cortex and cerebellum, the mice showed other significant effects such as a decrease in body weight and a lifespan of only 15 to 16 months. Thus, the scientists were unable to study other Parkinson’s-related effects such as changes in behavior and movement nor were they able to conduct a long-term analysis of how LRRK’s absence affects the brain.

Interestingly, the most common disease-linked mutation in LRRK2 is thought to make the protein more active. As a result, most efforts to develop a treatment against that mutation have focused on inhibiting LRRK2 activity.

“The fact that the absence of LRRK leads to the death of dopamine-containing neurons suggests that the use of inhibitory drugs as a treatment for Parkinson’s disease might not be the best approach,” said Dr. Shen.

Dr. Shen and her colleagues are now developing mice that have LRRK1 and 2 removed only in the dopamine-containing neurons of the brain. This specific deletion will allow the researchers to study longer-term and behavioral changes while avoiding the other consequences that lead to a shortened lifespan.

 

Research article: Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

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By IMPC

Published 7th July 2018

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