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Exploring Precision Microbiome Editing with CRISPR to Combat Diseases

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In a recent TED Talk featured on NPR, Nobel Prize-winning biochemist Jennifer Doudna discussed the transformative potential of CRISPR technology in treating complex diseases by targeting the human microbiome—the vast community of bacteria and microbes living in and on our bodies. Doudna, renowned for her co-discovery of the CRISPR-Cas9 gene-editing tool, highlighted how this technology can act like a "scalpel," allowing scientists to edit specific genes within particular microbes without disrupting entire microbial communities. This precision offers promising avenues for noninvasive therapies against conditions such as asthma, Alzheimer's, obesity, and diabetes, all of which have been linked to dysfunctional gut microbiomes.

Doudna emphasized that combining CRISPR with metagenomics—a technique that maps out microbial communities—can create a new field called precision microbiome editing. This approach has significant implications not only for human health but also for environmental sustainability. For instance, modifying the microbiomes of livestock could reduce methane emissions by up to 80%, addressing a significant contributor to climate change. By editing microbiomes at birth, these interventions could have long-lasting effects without ongoing treatments.

Mouse models are instrumental in advancing Doudna's goals of precision microbiome editing. They provide a controlled environment to study the effects of specific genetic modifications on complex biological systems. Using mouse models, researchers can observe how altering particular genes within the microbiome impacts disease development and progression. This accelerates the development of safe and effective CRISPR-based therapies before they are considered for human trials. The insights gained from these models are crucial for translating precision microbiome editing from the laboratory to real-world applications, ultimately helping to build a more resilient future for human health and the planet.

For the full transcript of Jennifer Doudna's talk, visit NPR.

MiniMUGA Genotyping Tool Updated to Improve Accuracy in Mouse Research

The MiniMUGA genotyping array, a vital tool for genetic quality control in laboratory mice, has been updated to improve its performance. Used in over 40,000 genotyping tests, MiniMUGA helps research programs like the Collaborative Cross (CC) and the Mutant Mouse Resource and Research Centers (MMRRC). The latest updates fix previous limitations and enhance the accuracy of genetic analysis by improving marker annotation, consensus genotypes, and the informatics pipeline.

These updates address key limitations in the original analysis pipeline, increasing the reliability of marker annotation and improving the consensus genotypes for a broader set of inbred strains. Using over 8,500 new samples, the revised pipeline enhances the identification and quantification of specific genetic backgrounds and includes important features such as chromosomal sex determination and construct detection.

Key Improvements

These updates to the MiniMUGA genotyping array are expected to benefit a wide range of mouse research applications. The improved rigor and reproducibility in genetic analysis will contribute to more reliable research outcomes in genetics, disease mechanisms, and therapeutic development. MiniMUGA’s ability to provide detailed genetic backgrounds and substrain-specific diagnostics makes it a valuable tool for maintaining the integrity of laboratory mouse colonies and supporting global research.

For more information, visit the unlocked article here.

Researchers Recommend Verifying Gene Disruption in Knockout Mice Due to En2 Insertions

A recent study highlights the importance of confirming gene disruption in knockout mice that use the "knockout-first" allele design. This approach, developed by the International Knockout Mouse Consortium, incorporates the En2 splice acceptor sequence and the lacZ reporter gene to facilitate gene function studies. While intended to disrupt gene function by interfering with normal splicing, the En2 sequence can sometimes be included in the host gene's mRNA. This inclusion may lead to the production of a mutant protein, resulting in partial gene activity rather than a complete knockout.

The researchers conducted a comprehensive computational analysis of over 14,000 mouse protein-coding genes with established knockout-first embryonic stem cell lines. They examined transcripts from 35 mutant lines and found that in 24 of these lines, the En2 sequence was present in the transcripts. This suggests that gene disruption might not be complete in these cases, potentially affecting the outcomes of experiments relying on these models.

Notably, the study did not find widespread effects on mouse phenotypes due to the predicted En2 insertion. However, the potential for partial gene activity underscores the need for researchers to verify the transcripts of their mutant mice. By confirming whether the En2 insertion is present, scientists can ensure that gene function is adequately disrupted, enhancing the reliability of their experimental results.

The study advises that mutant transcripts be checked for the En2 insertion and any leaky transcription when using knockout-first alleles. This additional step can help researchers avoid unintended consequences and maintain the integrity of studies.

For more details, read the full study here: https://link.springer.com/article/10.1007/s00335-024-10071-2

MMRRC Celebrates 25 Years of Impacting Biomedical Research

We proudly announce that the Mutant Mouse Resource and Research Centers (MMRRC) consortium has been featured in a recent Mammalian Genome publication, recognizing 25 years of advancing scientific research. This milestone reflects our dedication to providing the global research community access to a comprehensive collection of genetically engineered mouse strains. Our work supports various studies in genetics, cancer, and neurodegenerative diseases.

Supported by the National Institutes of Health (NIH), the MMRRC has become an essential resource for researchers seeking reliable and well-characterized mouse models. Our commitment to quality control, cryopreservation, and distribution has been instrumental in ensuring the reproducibility and reliability of research outcomes. We continue to innovate and expand our services to meet the evolving needs of the scientific community.

As we look forward to the future, the MMRRC remains committed to supporting transformative research that drives discoveries and improves human health. We'd like to invite you to explore the full publication in Mammalian Genome to learn more about our impact and vision for the future.

New Study Reveals Sex-Specific Brain Changes in Alzheimer's Disease, Offering Hope for Targeted Treatments

A recent study offers key insights into how Alzheimer's disease (AD) affects brain cells critical for memory. The research focused on hippocamposeptal (HS) neurons, which help the brain communicate between memory-related regions. By studying changes in these neurons in male and female mice, scientists discovered sex-specific differences in how AD progresses, which could lead to more targeted therapies.

Importantly, the research relied on genetically engineered mice provided by the Mutant Mouse Resource & Research Centers (MMRRC). These mice, especially the 5XFAD strain, are valuable for modeling Alzheimer's disease, allowing researchers to closely examine how AD pathology develops. This not only enhances our understanding of AD but also paves the way for new interventions that could slow or prevent memory loss.

The use of MMRRC mice in this study underscores their importance in advancing neuroscience research and the study of neurodegenerative diseases like Alzheimer's. The findings provide a better understanding of how specific brain circuits are disrupted in AD, potentially benefiting the development of treatments for millions affected by the disease.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364565/

MMRRC Model: https://www.mmrrc.org/catalog/sds.php?mmrrc_id=34840

Improving Reproducibility in Animal Research: The LAG-R Framework

The biomedical research community is tackling the persistent challenge of reproducibility in animal studies head-on with a suite of new measures designed to enhance scientific rigor. Key among these measures are standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. While the ARRIVE guidelines have made strides in setting documentation standards for laboratory animals, a critical gap remains: incomplete genetic information.

Enter the Laboratory Animal Genetic Reporting (LAG-R) framework. This innovative approach aims to thoroughly document the genetic makeup of animals used in scientific research, providing essential details that ensure experiments can be replicated accurately and models used appropriately. LAG-R focuses on comprehensive documentation of genetic backgrounds, modifications, and validation processes, which are crucial for interpreting and replicating experimental results.

The benefits of LAG-R are substantial. Standardizing genetic information documentation enhances the reproducibility of studies, making peer reviews more reliable and reducing the risks of misinterpretation. Additionally, LAG-R promotes data sharing, fostering collaboration across laboratories and institutions and ensuring consistent use of animal models with well-documented genetic backgrounds.

Furthermore, LAG-R supports the responsible use of research resources. The framework saves valuable time and resources by reducing redundant experiments and improving the ethical management of animal use through precise experimental planning. While verifying every genetic detail of research animals may be impractical, improved reporting and validation efforts will significantly boost research reliability.

This initiative marks a significant step towards ensuring the accuracy and dependability of animal studies, ultimately advancing scientific discovery. By enhancing transparency and thoroughness in genetic reporting, the LAG-R framework will support the development of more reliable and reproducible research models. This is a win for the entire scientific community, paving the way for groundbreaking advancements in biomedical research.

Source: https://www.nature.com/articles/s41467-024-49439-y?utm_source=rct_congratemailt&utm_medium=email&utm_campaign=oa_20240703&utm_content=10.1038/s41467-024-49439-y

New Study Highlights Role of MMRRC Mice in Migraine Research

A recent study has made a significant breakthrough in understanding the mechanisms behind migraine headaches. It revealed the pivotal role of specific mouse models provided by the Mutant Mouse Resource & Research Centers (MMRRC). This research identifies the PACAP38-MrgprB2 pathway as a crucial factor in stress-induced migraine.

Study Overview

Migraine headaches, affecting approximately 15% of the global population, remain a poorly understood yet highly disruptive condition. Researchers have now demonstrated that increased pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) due to stress can induce headache-like behaviors in mice. This discovery sheds light on how migraines may serve as a warning signal for stress-induced homeostatic imbalances.

Methodology and Key Findings

The study utilized PAC1 conditional knockout (KO) mice, generated by crossing C57BL/6N-Atm1BrdAdcyap1r1tm1a(KOMP)Wtsi/MbpMmucd mice (RRID:MMRRC_046500-UCD) with B6N(B6J)-Tg(CAG-Flpo)1Afst/Mmucd mice (RRID:MMRRC_036512-UCD). These mice were essential in investigating the PACAP38-MrgprB2 pathway.

Researchers found that increased levels of PACAP38, resulting from repetitive stress, caused MrgprB2-dependent headache behaviors. This effect was mediated by mast cell degranulation, which sensitized trigeminal ganglion neurons. Blocking this pathway successfully prevented the development of headache behaviors in the mice.

Implications for Migraine Treatment

This study highlights the PACAP38-MrgprB2 pathway as a promising target for new migraine treatments, particularly stress-related ones. Understanding this pathway provides critical insights into the biological mechanisms that cause migraines and opens new avenues for therapeutic development.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131290/

MMRRC Mice Used:

https://www.mmrrc.org/catalog/sds.php?mmrrc_id=46500

https://www.mmrrc.org/catalog/sds.php?mmrrc_id=36512

In groundbreaking research, scientists have elucidated the effects of neuroinflammation on brain metabolism in Alzheimer's disease using the APPswe/PS1dE9 mouse model (MMRRC Strain # 034829). This study promises to enhance early diagnostic methods and the development of targeted treatments.

Methodology

Employing in vivo 2-photon microscopy alongside the Oxyphor 2P oxygen sensor, the team measured oxygen levels and capillary blood flow in the brains of mice before and after inducing neuroinflammation with lipopolysaccharide (LPS). Initially, Alzheimer's mice exhibited a lower metabolic demand than healthy counterparts, with similar capillary blood flow across both groups.

Results

After the LPS treatment, both groups showed significant decreases in oxygen levels with increased oxygen extraction, while capillary flow remained stable. These findings suggest that neuroinflammation primarily affects brain metabolism rather than blood flow, underlining its potential as a target for early intervention in Alzheimer's progression.

Broader Implications

The implications of this study extend beyond Alzheimer's disease, potentially offering insights into other conditions where neuroinflammation affects cognitive functions. This research underscores the importance of targeting inflammation in early therapeutic strategies and invites further investigation into the complex interactions between neuroinflammation and cerebral energetics.

References

Paper Source: 10.1186/s13195-024-01444-5
Mouse Model: APPswe/PS1dE9

Unveiling the Power of Neuronal Growth Cones with MMRRC Mice

Groundbreaking research has shed light on the crucial role of growth cones in neuron migration, utilizing various mouse models, including a model supplied by the Mutant Mouse Resource & Research Centers (MMRRC). The dynamic structures of cones, pivotal in navigating the neuronal landscape, demonstrate the intricacies of brain development and repair processes.

Key Insights:

Conclusion:

The use of MMRRC mice in this study has been instrumental in advancing the understanding of neuronal growth cones and their role in brain development and repair. By exploring the sophisticated mechanisms of neuron migration, this research paves the way for innovative treatments to enhance brain healing and functional recovery, marking a significant milestone in neuroscience.

Publication: Identification of the growth cone as a probe and driver of neuronal migration in the injured brain

Mouse Model Used: STOCK Tg(Dcx-EGFP)BJ224Gsat/Mmmh

Groundbreaking Study Unveils Potential Neuropathic Pain Treatment, NIH Director Applauds Efforts

NIH-Funded Study at UT Austin Opens New Doors for Neuropathic Pain Treatment with MMRRC Models.

In a significant development, researchers at the University of Texas at Austin, supported by the National Institutes of Health (NIH), have identified a promising new approach to treating neuropathic pain. Highlighted by the NIH's new director, Dr. Monica M. Bertagnolli, the study utilized mice from the Mutant Mouse Resource & Research Centers (MMRRC) and the Knockout Mouse Program (KOMP) to explore innovative treatment methods.

The research focused on a specific molecule capable of binding to a protein closely involved in the mechanisms of neuropathic pain, a condition that affects millions worldwide. This binding has been shown to reduce the hypersensitivity to pain caused by nerve damage, offering a beacon of hope for those suffering from this chronic condition.

Dr. Bertagnolli emphasized the importance of this discovery, noting the critical role of NIH-funded research in advancing medical science and improving patient outcomes. The use of MMRRC mice was pivotal, demonstrating the value of these resources in facilitating high-quality research.

This breakthrough represents a vital step in developing more effective treatments for neuropathic pain, underscoring the significance of collaboration and investment in scientific research.

NIH Director Announcement: https://twitter.com/NIHDirector/status/1757170335361982975

Paper Reference: https://www.pnas.org/doi/10.1073/pnas.2306090120

Mouse Model Used: https://www.mmrrc.org/catalog/sds.php?mmrrc_id=50147

MMRRC Leads the Way in Enhancing Biomedical Research Through Improved Citation Practices

The Mutant Mouse Resource & Research Centers (MMRRC) has again demonstrated its pivotal role in advancing biomedical research. A recent review spanning a decade has highlighted the significant strides made in citation practices for research resources, particularly in the context of transgenic animals and antibodies, with the MMRRC at the forefront of this progress.

Background
In biomedical research, resources like transgenic animals and antibodies are essential. Their effective utilization and tracking hinge on the accuracy and consistency of citation practices. Historically, this has been a challenge due to inadequate systems for tracking resource usage, leading to approximately 50% of these resources being not easily findable in academic literature.

The RRID Initiative and MMRRC's Role
The Resource Identification Initiative (RRID) has collaborated with journals and resource providers to refine citation practices to address this crucial gap. The MMRRC, a key player in this initiative, has been instrumental in promoting the use of RRIDs (Research Resource Identifiers) among the scientific community.

Key Findings from the Review
The review, covering ten years of citation data from five university-based stock centers, revealed:

Impact and Future Outlook
This advancement in citation practices, championed by the MMRRC, not only facilitates better tracking and reproducibility of research but also aligns with the National Institutes of Health's (NIH) emphasis on research rigor and transparency. The MMRRC's efforts reflect a broader commitment to enhancing the quality and reliability of biomedical research.

"We are proud to be at the vanguard of this significant change in the research community," said a spokesperson for the MMRRC. "Improving the way we cite and track research resources is not just about better record-keeping; it's about enhancing the integrity and reproducibility of scientific research, which is at the heart of our mission."

For more information, visit https://doi.org/10.1101/2024.01.15.575636.

MMRRC Models Help Explore NFIA Gene Role in Retinal Cell Development

In the complex and fascinating realm of retinal cell biology, a recent groundbreaking study has illuminated the crucial role of the NFIA gene in the development of retinal cells, specifically focusing on a particular type of cell known as the AII amacrine cell. This cell type is fundamental in the intricate network of the eye, playing a significant role in processing visual information.

Understanding AII Amacrine Cells

AII amacrine cells are specialized neurons in the retina, the light-sensitive layer lining the back of the eye. These cells are indispensable in the visual system, playing a critical role in the processing and interpreting of visual signals. They contribute substantially to our visual acuity and our overall perception of the visual world.

The Crucial Role of the NFIA Gene

Through advanced research utilizing mouse models, particularly those provided by the Mutant Mouse Resource and Research Centers (MMRRC), the NFIA gene has emerged as a pivotal factor in developing AII amacrine cells. Studies indicate that when the NFIA gene is inactive or dysfunctional, there is a marked reduction in the population of these essential retinal cells.

Broad Implications of the Research

The consequences of fewer AII amacrine cells extend beyond a simple reduction in cell count. This deficiency can lead to significant alterations in the overall functionality of the retina, potentially impacting various aspects of eye health. This new understanding is crucial for comprehending various ocular conditions and diseases, opening new possibilities for exploring treatments for retinal disorders originating from cellular development issues.

Advancing Eye Health Research

This research represents a significant leap forward in understanding the complex interplay between genetics and cellular biology in our bodies. Gaining insights into the role of specific genes, such as NFIA, in developing retinal cells is vital for medical science. It holds immense potential for developing treatments for a range of eye diseases.

Future Prospects in Neurodevelopment and Retinal Research

The findings from this study lay the groundwork for further exploration in the vast neurodevelopment and retinal research field. As scientists continue to unravel the complexities of the eye and its cellular makeup, we move closer to groundbreaking advancements that could revolutionize our approach to eye health treatment and understanding. This research adds to our knowledge of the eye and opens doors to potential innovations in medical science, particularly in the realm of ophthalmology and neurobiology.

Find this study here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10711738/

MMRRC Mice Illuminate STAT1's Role in Enhancing Post-Stroke Recovery

When it comes to stroke recovery, understanding the cellular mechanisms at play is a critical step towards developing effective therapies. A recent groundbreaking study, utilizing mice from the Mutant Mouse Resource and Research Centers (MMRRC), has provided deeper insights into these mechanisms, shedding light on the role of the transcription factor signal transducer and activator of transduction 1 (STAT1) in ischemic stroke recovery.

STAT1 and Stroke: An Evolving Understanding

The connection between STAT1 and ischemic stroke has been established, with STAT1 known to contribute to acute neuronal death within the first 24 hours. However, the impact of STAT1 on brain microglia and macrophages (Mi/MΦ) - cells that can shift to a harmful or advantageous phenotype following a stroke - and its influence on long-term recovery were previously unknown.

To unravel this mystery, researchers turned to MMRRC mice. They generated a model featuring a tamoxifen-induced, Mi/MΦ-specific knockout (mKO) of STAT1, and then induced ischemic stroke via a procedure known as transient middle cerebral artery occlusion (MCAO).

Inflammation and Recovery: The Key Role of STAT1

The study showed that STAT1 was activated in Mi/MΦ three days after MCAO - the subacute stage of stroke. Intriguingly, selective deletion of STAT1 in these cells did not alter neuronal cell death or infarct size within the first 24 hours post-MCAO. Instead, it bolstered the release of high mobility group box 1 and increased the production of arginase 1-producing Mi/MΦ three days after MCAO, suggesting an amplified inflammation-resolving response.

The implications of this for long-term post-stroke recovery were substantial. MMRRC mice with STAT1 mKO exhibited less brain inflammation in the subacute stage post-MCAO and reduced long-term white matter injury. This improved functional recovery for at least five weeks post-MCAO, a benefit seen in both male and female mice.

STAT1: A Promising Target for Therapeutic Intervention

The findings suggest that while Mi/MΦ-targeted STAT1 KO does not offer immediate neuroprotection, it does augment the inflammation-resolving actions of Mi/MΦ, facilitating long-term functional recovery after stroke. This points to STAT1 as a promising therapeutic target for harnessing beneficial Mi/MΦ responses and improving long-term outcomes for ischemic stroke patients.

The use of MMRRC mice in this groundbreaking research provides invaluable insights into post-stroke recovery mechanisms. The results could lead to innovative therapeutic approaches for treating ischemic stroke, making the study a beacon of hope for medical professionals and patients alike.

Source: https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02860-4

Unveiling the Mysteries of the Brain: Understanding the Striatum and Subthalamic Nucleus Interaction with MMRRC Mice

In a groundbreaking study, neuroscientists have made significant strides in understanding the relationship between two key areas of the brain, the striatum and the subthalamic nucleus (STN), both integral parts of the basal ganglia system. The study, which was performed on adult male and female mice from the Mutant Mouse Resource & Research Centers (MMRRC), delves into the detailed interaction and organization of the subthalamostriatal projections - direct axonal connections from the STN to the striatum.

To comprehend this complex interplay, the researchers implemented monosynaptic retrograde tracing from specific populations of dorsal striatal neurons. They aimed to quantify the connectivity from STN neurons to various striatal cell types, including spiny projection neurons, GABAergic interneurons, and cholinergic interneurons.

In the study, the team combined ex vivo electrophysiology and optogenetics to decipher the responses of diverse dorsal striatal neuron types to the activation of STN axons. Remarkably, their findings revealed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons was significantly higher (approximately 4 to 8 times) than that from STN to any of the other striatal cell types examined.

Further, only parvalbumin-expressing interneurons exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs, corroborating the tracing studies' results. The data collectively demonstrate the selectivity of the subthalamostriatal projection for the target cell type, an important finding in neurobiology.

In summary, the study underscores the unique position of glutamatergic STN neurons, highlighting their potential to directly and powerfully influence striatal activity dynamics due to their enriched innervation of GABAergic parvalbumin-expressing interneurons. These findings, generated using mice from the MMRRC, contribute substantially to our understanding of brain dynamics and open new avenues for exploring neurological disorders and potential treatments.

Source: https://www.eneuro.org/content/10/7/ENEURO.0417-21.2023

Neurodevelopmental disorders and SCN2A

Neurodevelopmental disorders (NDD) represent a broad spectrum of conditions disrupting typical neurological growth and development. One gene, SCN2A, has been closely linked to various disorders. Pathogenic variants in SCN2A are monogenic, meaning they originate from alterations in a single gene. However, the phenotypic manifestations of these variants — the observable physical and behavioral traits — show a high degree of variability, often puzzling clinicians and researchers alike. This has led to a comprehensive investigation into the complex genotype-phenotype correlations underlying SCN2A-related NDD.

Studying genetic modifiers

One way to unravel these complex correlations is to study genetic modifiers. These are genes that can impact the expression of another gene. In the context of rare driver mutations such as those in SCN2A, genetic modifiers can contribute to the considerable variability in disease phenotypes. A standard method to study this is using inbred rodent strains, which exhibit different genetic backgrounds and provide a unique opportunity to observe and analyze the influence of these backgrounds on disease-related phenotypes. Mice used in this research were obtained from the Mutant Mouse Resource & Research Centers (MMRRC), a trusted source for mouse models of human disease.

Development of a mouse model

The recent study developed a mouse model of the SCN2A-p.K1422E variant maintained as an isogenic line on the C57BL/6J (B6) strain. Upon initial characterization, the heterozygous Scn2aK1422E mice showed alterations in anxiety-related behavior and seizure susceptibility, a finding that provided a preliminary view of the phenotypes linked with the SCN2A mutation.

The researchers compared the neurobehavioral assays from mice on the B6 strain with those on a [DBA/2J×B6]F1 hybrid (F1D2) strain to explore how the genetic background could influence these phenotypes. The intriguing results showed that Scn2aK1422E mice displayed lower anxiety-like behavior than their wild-type counterparts. Interestingly, this effect was more pronounced on the B6 background than on the F1D2 background.

They also evaluated strain-dependent differences in seizure activity. Although there were no noticeable differences in the occurrence of rare spontaneous seizures between the two strains, the response to the chemo-convulsant kainic acid did show differences. This difference was not only in seizure generalization but also in the risk of lethality and varied based on both strain and sex of the mice.

Implications of the research

The implications of our research are significant. Continued exploration of strain-dependent effects in the Scn2aK1422E mouse model could highlight genetic backgrounds with unique susceptibility profiles. These insights would be precious for future studies, specifically, those focused on identifying specific traits associated with SCN2A-related NDD.

Moreover, by shedding light on the most penetrant phenotypes and potential modifier genes, researchers hope to unearth clues about the primary pathogenic mechanism of the K1422E variant. Such information is paramount for developing novel treatment strategies and personalized medicine approaches for patients with these challenging conditions. In conclusion, by tapping into the potential of mouse models, science can advance understanding of the genetic intricacies of SCN2A-related NDD.

Source: https://via.hypothes.is

Researchers have released the first-ever mouse-specific reference ranges for electrocardiography (ECG) in a monumental advancement for the scientific community. This pioneering work is set to significantly enhance diagnostic decision-making in clinical medicine and our understanding of normality in pre-clinical scientific research involving in vivo models.

This breakthrough is backed by a robust dataset derived from over 26,000 laboratory mice, making it one of the most comprehensive ECG studies involving mice. These data were collected from C57BL/6N wildtype control mice, with the findings stratified by sex and age, adding to the robustness of the developed ECG reference ranges.

What makes this study genuinely groundbreaking are the intriguing findings revealed. The researchers reported minimal sexual dimorphism in heart rate and critical elements from the ECG waveform. This means no significant differences between male and female mice were observed in these parameters.

Furthermore, as expected, anesthesia was shown to induce a decrease in heart rate. This was observed for inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. Such insights will be crucial for experiments where anesthesia is required, allowing researchers to account for these effects in their analysis.

In another important finding, researchers did not observe significant age-related ECG changes in C57BL/6N-inbred mice. The differences in the reference ranges of 12-week-old mice compared to 62-week-old mice were negligible, suggesting that age has a minimal impact on these ECG parameters in this mouse strain.

To test the generalizability of these reference ranges, they were compared with ECG data from a wide range of non-International Mouse Phenotyping Consortium (IMPC) studies. The close overlap in data from a wide variety of mouse strains suggests that these reference ranges have broad applicability and can serve as a robust and comprehensive indicator of normality.

This unique ECG reference resource offers a significant advantage for any experimental study of cardiac function in mice. The ability to compare observed data with robust, mouse-specific ECG reference ranges will significantly enhance the quality and reliability of future cardiac studies. It is a groundbreaking leap in mouse cardiac research with immense potential for future discoveries.

Read the full paper here to dive deeper into these exciting findings.

Unraveling the Complex Role of GABAARs in Adult Brain Neurons Using MMRRC Mice

GABAA receptors (GABAARs) are crucial components of our brain's communication system. They are involved in controlling the activity of neurons, including striatal spiny projection neurons (SPNs). However, the exact role of GABAARs in synaptic integration, particularly in adult SPNs, remains less understood. In a recent study, researchers employed a range of techniques using MMRRC mice to provide new insights into the complex interactions between GABAARs and another type of receptor, ionotropic glutamate receptors (iGluRs), in regulating neuron function.

Methods:

To explore the role of GABAARs in adult SPNs, the researchers used a combination of molecular, optogenetic, optical, and electrophysiological approaches on ex vivo brain slices from MMRRC mice. Computational tools were also employed to model somatodendritic synaptic integration, which is the process by which neurons combine multiple signals.

Results:

The study found that activating GABAARs caused currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Interestingly, this relatively positive reversal potential was not attributed to the expression of a particular protein (NKCC1), but rather to a balance between two other transporters (KCC2 and Cl-/HCO3-cotransporters).

When researchers activated GABAergic synapses, they observed that SPNs became depolarized from their resting down-state. This GABAAR-mediated depolarization worked together with the stimulation of ionotropic glutamate receptors (iGluRs), leading to increased somatic depolarization and dendritic spikes.

Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. This finding suggests that GABAARs and iGluRs can work in concert to excite adult SPNs when they are in a resting down-state. The inhibitory role of GABAARs appears to be limited to brief periods near the spike threshold.

Implications:

The results of this study call for a reevaluation of the role of GABAARs in intrastriatal GABAergic circuits. The discovery that GABAARs can work in conjunction with iGluRs to excite adult SPNs in their resting down-state suggests a more complex role in regulating neuron function than previously thought.

By using MMRRC mice and a variety of techniques, the researchers have provided valuable insights into the intricate interactions between GABAARs and iGluRs in adult brain neurons. This knowledge could potentially lead to a better understanding of various neurological disorders and contribute to the development of more effective treatments.

Conclusion:

The study using MMRRC mice has shed light on the complex role of GABAARs in adult striatal spiny projection neurons. By demonstrating that GABAARs can work together with iGluRs to excite adult SPNs in their resting down-state, researchers have opened up new avenues for understanding the regulation of neuronal function and the potential implications for neurological disorders.

Source: https://www.biorxiv.org/content/10.1101/2023.03.14.532627v2

Insights from MMRRC Mice on Genome Function and Development

Imagine the genome as a city with different neighborhoods, each having its function. Topologically associating domain (TAD) boundaries are like the fences that separate these neighborhoods, maintaining distinct regulatory territories. Disruption of these boundaries may interfere with regular gene expression and cause diseases, but the full impact remains unclear.

Researchers utilized CRISPR genome editing in mice to investigate the consequences of deleting eight TAD boundaries. All deletions led to noticeable molecular or organismal phenotypes, including chromatin interaction or gene expression changes, reduced viability, and anatomical abnormalities.

In 88% of cases, local 3D chromatin architecture was altered. This included merging TADs and changed contact frequencies within adjacent TADs. Additionally, 63% of the examined loci exhibited increased embryonic lethality or developmental issues. For instance, a TAD boundary deletion near Smad3/Smad6 led to complete embryonic lethality, while another near Tbx5/Lhx5 caused severe lung malformation.

This study highlights the importance of TAD boundary sequences for proper genome function and organism development. It also emphasizes the need to consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. By understanding the impact of TAD boundary disruptions, we can better diagnose and potentially treat genetic disorders.

Source: https://www.nature.com/articles/s42003-023-04819-w#Sec8

MMRRC Mice Help Discover New Molecular Connections in Heart Failure

Heart failure affects millions worldwide. Recently, a groundbreaking study has revealed the relationship between three molecules—MIAT, miR-150, and Hoxa4—which could hold the key to new treatment strategies for heart failure patients.

The Study:

Researchers used genetically modified mice from the Mutant Mouse Resource & Research Center (MMRRC) to investigate the roles of MIAT, miR-150, and a novel target, Hoxa4, in heart failure. The mice were subjected to a model of myocardial infarction and various tests to evaluate their cardiac function and molecular mechanisms.

Key Findings:

The study found that increasing MIAT levels worsened cardiac damage while deleting MIAT protected the mice's hearts. Importantly, increasing miR-150 levels helped counteract MIAT's harmful effects. The scientists also identified Hoxa4 as a new downstream target of the MIAT/miR-150 pathway and discovered that mice lacking Hoxa4 exhibited protection from myocardial infarction.

Conclusion:

This research unveiled a crucial interaction among MIAT, miR-150, and Hoxa4, providing valuable insights into a novel regulatory mechanism involved in heart failure. Understanding these molecular connections could pave the way for new treatments targeting these molecules, offering hope to heart failure patients worldwide. The study also highlights the importance of using genetically modified mice in advancing our knowledge of complex diseases like heart failure.

https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.121.008686

Database of Phenotyped KO Mice Identifies New Genes for Rare Disease Research Opportunities

The search for new treatments and cures for rare diseases is an ongoing challenge for researchers worldwide

One of the key strategies in this effort is the identification of genes that may be implicated in these diseases, particularly those involved in ciliopathies - a group of rare genetic disorders caused by defects in the function or structure of cilia.

At the MMRRC, we constantly explore innovative ways to advance medical research and improve patient outcomes. A recent study used the International Mouse Phenotyping Consortium (IMPC) database of single-gene knockout (KO) mice to identify candidate ciliopathy genes. These mice are found and available from the MMRRC.

The approach involved screening mouse lines with ocular, renal, or reproductive trait abnormalities for phenotypes. Then, the STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains. This allowed generation of a list of "candidate ciliopathy genes" - 32 genes encoded proteins that were predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology.

To provide evidence of the potential clinical relevance of these candidate genes, histological and morphological data was presented from knockout mouse lines with phenotypes resembling those found in ciliopathies. These included genes such as Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1.

The study demonstrates the power of the IMPC phenotype data for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. By uncovering genes with no previously known role in ciliary biology, new avenues for research and potential treatments for ciliopathies are open for discovery.

At the MMRRC, we are committed to advancing medical research and improving patient outcomes. Our study is just one example of the innovative research being conducted in our labs every day. Stay tuned for more exciting developments in the search for new treatments and cures for rare diseases.

https://doi.org/10.1038/s41598-022-19710-7

Higgins, K., Moore, B.A., Berberovic, Z. et al. Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes. Sci Rep 12, 20791 (2022).

A Review of Gene Database Reveals Unique, Unreported Associations with Eye Defects and New Pathways for Ocular Gene Research

Mutant mouse genetic modifications have revolutionized biomedical research, enabling scientists to study specific gene mutations and their effects on biological processes. This study used data mining to investigate congenital abnormalities underlying the Microphthalmia, Anophthalmia, and Coloboma (MAC) spectrum disease, a group of eye malformations that cause childhood visual impairment.

The research involved a systematic forward screening of the mammalian genome, using the International Mouse Phenotyping Consortium (IMPC) database to identify knockout lines with genetically associated eye defects in mouse embryos. The IMPC database is a valuable resource for researchers, as it contains a vast array of information on knockout mouse models and associated phenotypes.

Data mining efforts identified 74 unique knockout lines (genes) with ocular abnormalities, most of which were small or absent eyes - findings most relevant to MAC spectrum disease in humans. Of these 74 lines, 27 had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. This left 12 previously published gene knockouts with no reported ocular abnormalities and 47 unpublished knockouts with ocular abnormalities identified by the IMPC. These represented 59 genes not previously associated with early eye development in mice.

Further analysis identified 19 of these genes with a reported human eye phenotype, demonstrating the clinical relevance of our findings. In total, 40 previously unimplicated genes linked to mammalian eye development were identified, highlighting the power of mutant mouse genetic modifications in identifying novel gene targets for rare diseases.

Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Notably, analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation.

The findings provide a valuable resource for researchers investigating the genetic abnormalities underlying MAC spectrum disease and other congenital blinding diseases. Using data mining and mutant mouse genetic modifications, novel genes and pathways required for early eye development are open for further research application. These findings can potentially accelerate the diagnosis and treatment of these rare diseases.

https://doi.org/10.1186/s12915-022-01475-0

Chee, J.M., Lanoue, L., Clary, D. et al. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development. BMC Biol 21, 22 (2023).

Collaborative Cross Mice now Available at the MMRRC

The Mutant Mouse Resource and Research Center (MMRRC), the official National Institute of Health (NIH) repository of mouse models, is pleased to announce the availability of the Collaborative Cross mouse population for distribution. The Collaborative Cross (CC) is a multi-parental genetic reference mouse population derived from eight founder inbred strains, encompassing an extraordinary level of genetic diversity. The CC is an ideal population for studying complex traits and for identifying novel models of disease in the context of natural genetic variation.

This newly acquired collection has been deposited into the MMRRC at UNC. These strains have been available through the Systems Genetics Core Facility (SGCF) at UNC since 2012. The breeding of the CC lines started with 8 inbred founders obtained from the Jackson Laboratory. Breeding was performed at Oak Ridge National Laboratory in Tennessee, International Livestock Research Institute (ILRI) in Kenya, Geniad, Ltd in Western Australia, and the Jackson Laboratory.

The CC collection is composed of 63 strains. Each CC strain has deep and uniform genetic characterization including MiniMUGA consensus genotypes, haplotype mosaics, and whole genome sequences. All but 8 strains are >95% inbred as of 2020 (range 88-100%). The CC strains are listed on the MMRRC’s website (here).

Experimental cohorts and breeding pairs/trios are available. The CC collection is maintained as repository live (i.e., continuously bred). Note that breeding productivity and order queues can affect fulfillment dates, and the MMRRC may recommend delivery of orders in batches. For ordering inquiries, please contact MMRRC_CC@unc.edu.

COVID-19 is a serious public health threat and researchers around the globe are turning to mouse models as a critical tool in viral pathogenesis, vaccine, and drug treatment discovery research. To help support these efforts, the MMRRC is distributing several COVID-19 related mouse models. To learn more about the COVID-19 related list of available strains available from the MMRRC, please visit: https://www.mmrrc.org/catalog/covid_models.php

MARC1 - the barcoding lines are now available in the MMRRC!

The MMRRC is now maintaining two exciting new lines with broad applicability and interest to scientists working in many different areas. These mouse lines are called “Mouse for Actively Recording Cells 1” or MARC1. Donated by Dr. George M. Church, Ph.D., and Dr. Reza Kalhor, Ph.D., of Harvard Medical School, they are used for barcoding and lineage tracing applications in the mouse (PMID:30093604). Although these lines do not express any disease-related phenotypes, when a MARC1 mouse is crossed to mice expressing cas9 (universally or in a lineage-specific manner), combinatorial and cumulative barcoding starts in the progeny during their development, leading to developmentally barcoded animals that can be used for a multitude of applications, including lineage tracing.

The available lines are:

Please contact our customer service center at service@mmrrc.org if you have any questions about these new lines.

January is Health and Awareness of Birth Defects Month

This month seeks to promote health and awareness of birth defects. At the MMRRC, we understand that data sharing is essential to speed translation of research results into knowledge, therapies, and procedures to improve human health. The MMRRC is committed to sharing data and offers several strains and models to advance research in structural birth defects and foster discovery of shared genetic pathways between disorders:

https://www.nichd.nih.gov/about/overview/directors_corner/prev_updates/010715-birth-defects

Popular research models available in the MMRRC include:

Contact us if you need assistance with learning more about strains related to birth defects in the MMRRC repository.

Hybridoma Cell Lines into the MMRRC at UC Davis

The MMRRC is pleased to welcome its newest collection of cell lines to the repository. The UC Davis/NIH NeuroMab Facility has deposited 473 Hybridoma Cell Lines into the MMRRC at UC Davis.

Hybridoma cell lines are immortal monoclonal antibody producing cells that can be grown in tissue culture at any scale to produce monoclonal antibodies. Each of the 473 cell lines in the MMRRC produced monoclonal antibodies validated for the specificity and efficacy in brain research applications at UC Davis/NIH NeuroMab Facility.

This new collection will empower researchers with the ability to produce large quantities of specific and highly validated monoclonal antibodies at low cost. One of the other benefits of having this collection in the MMRRC is that scientists also have access to knockout mouse lines for genes that encode protein targets of the NeuroMAb monoclonal antibodies. Accessibility of these cell lines will allow investigators to explore the dynamic organization of specific cell antibodies critical to understanding and improving health and disease.

Check out the new collection here

MMRRC Announces Availability of KOMP Repository Mice & ES Cells

The Mutant Mouse Resource and Research Center (MMRRC), the official National Institute of Health (NIH) repository of mouse models, is pleased to announce the availability of genetically-altered mice and embryonic stem (ES) cells made as part of the NIH Knockout Mouse Project (KOMP) and previously maintained in the KOMP Repository. The KOMP Repository collection will provide investigators with the convenience of a one-stop portal to one of the largest inventories of mutant mouse strains and ES cell lines available to the biomedical research community.

These newly acquired mouse and ES cell lines have been deposited into the MMRRC at UC Davis. The MMRRC at UC Davis is the largest of four regional archive and distribution centers in the NIH consortium. The MMRRC functions as a single repository resource and is comprised of an Informatics, Coordination and Service Center (ICSC) and three additional regional distribution facilities which include: The Jackson Laboratory, University of Missouri, and University of North Carolina, Chapel Hill. The newly available KOMP Repository mice (4,175 unique lines) & ES cell lines (14,013 unique mutant lines and 7 parental lines) can be accessed by visiting the MMRRC website (www.mmrrc.org) and typing in "KOMP Repository" in the search function, or by using the advanced search function and indicating “Major Collection = KOMP", and then searching by gene of interest, which will allow filtering for ES cells or mice.

The MMRRC was created in 1999, and is supported through the NIH, Office of Infrastructure and Research Programs (ORIP), as the nation’s premier mouse archive and distribution repository. Since that time, the MMRRC has earned an international reputation for the management, cryopreservation, and distribution of scientifically valuable, genetically engineered mouse strains and mouse ES cells. In partnership with researchers around the globe, the MMRRC continues to expand its holdings of mouse models. Today, with more than 59,000 available models, the MMRRC serves as a valuable resource to drive research discoveries for human disease.

January is National Birth Defects Prevention Month

This month seeks to promote health and awareness of birth defects. At the MMRRC, we understand that data sharing is essential to speed translation of research results into knowledge, therapies, and procedures to improve human health. The MMRRC is committed to sharing data and offers several strains and models to advance research in structural birth defects and foster discovery of shared genetic pathways between disorders.

https://www.nichd.nih.gov/about/overview/directors_corner/prev_updates/010715-birth-defects

Popular research models available in the MMRRC include:

Contact us if you need assistance with learning more about strains related to birth defects in the MMRRC repository.

MMRRC Education & Outreach Booth Conference Wrap Up

The MMRRC education booth is back from two exciting end of the year conferences in San Diego: ASHG and SfN. Both conferences boasted strong attendance rates, with ASHG claiming their highest attendee count to date. There were many great poster sessions showcasing the latest research efforts involving the use of mouse models. We had the pleasure of meeting many new investigators and students and learning about their research efforts involving the use of mice. We were also excited to provide information about role that the MMRRC plays with archiving and distribution of mouse models, and the importance of rigor and reproducibility. It’s always great to see that our outreach and education efforts can have an impact on increasing awareness of the MMRRC.

#mousemodels #mouseresearch #rigorandreproducibility #NIHORIP #mouseresearchstudies #MMRRC #MMRRCMice #ASHG #ASHG2018 #ASHG18 #SFN2018 #SfN18

New MMRRC Submission Form Coming Soon!

The MMRRC is excited to announce the upcoming release of our newly redesigned submission form set for debut on Wednesday, May 2nd 2018.

Along with user-friendly navigation the form has been significantly reduced to only include the bare minimum criteria needed for strain acceptance. The new design allows users to navigate through the submission form easily and effectively with informative tool-tips to help explain and clarify questions.

Our new shorter form will reduce completion time significantly and make multiple submissions a much simpler process. We anticipate a smooth transition over and look forward to hearing your feedback!

MMRRC to attend ASHG in Orlando

Representatives from the MMRRC will be attending American Society of Human Genetics 2017 October 17 – 21 in Orlando FL. Please be sure to stop by our education and outreach booth and learn more about how the MMRRC can help you with your mouse related research needs.

http://www.ashg.org/2017meeting/

KOMP 2 Phase 2 Mouse Lines Available Through The MMRRC

Since 2006, researchers around the world have been working together to generate a targeted knockout mutation for every gene in the mouse genome. The US component of this effort, The Knockout Mouse Project (KOMP), has been providing critical tools for understanding gene function and the genetic causes of human diseases.

In 2016, the National Institutes of Health funded the next phase in the KOMP project called KOMP2 Phase 2 with the objective to produce and phenotype more than 3000 new knockout mouse lines on a C57BL6/N genetic background. Here at the MMRRC, we are pleased to announce that these KOMP2 Phase2 mouse lines will all be made available from the MMRRC repositories. New mouse lines will be added monthly and full phenotyping data will be available.

MMRRC attending ASCB 2014 in Philadelphia

Representatives of the Mutant Mouse Regional Resource Center will be attending the American Society of Cell Biology Meeting in Philadelphia December 6-10. Please come by booth #916 and let us help you with your mouse research needs.

dkNET Releases Version 1.2

The NIDDK Information Network (dkNET) serves the needs of basic and clinical investigators by providing seamless access to large pools of data relevant to the mission of The National Institute of Diabetes Digestive and Kidney Diseases (NIDDK). The dkNET portal contains information about research resources such as antibodies, vectors and mouse strains, data, protocols, and literature.

MMRRC updated order form

The MMRRC is pleased to officially announce the release of our newly redesigned order process! Along with user-friendly navigation and the new "Favorites" feature, the order form has been updated with the latest information and a fresh new look. The new design allows users to navigate through the order process easily and effectively with alerts for missed questions, in-line hints, and the ability to alter contact information within the form. The new Favorites feature allows users to save and organize their favorite products and even allows them to send their favorites list to their registered email account for later reference.

MMRRC now searchable by major MeSH terms

The Mutant Mouse Regional Resource Center (MMRRC) repository simple and advanced search methods now include the ability to search by associated Major Medical Subject Heading (MeSH) terms. MeSH is the National Library of Medicine\'s controlled vocabulary thesaurus. It consists of sets of terms naming descriptors in a hierarchical structure that permits searching at various levels of specificity. Major MeSH terms are defined by authors of primary research articles as having the most relevance to the research represented by the article.

IMPC Survey of the Mouse User Community

The International Mouse Phenotyping Consortium is conducting a survey with the goal of exploring ways to ensure that researchers utilize high-impact mouse-model resources. The on line survey is available here.

Gene found that regenerates heart tissue

Researchers at UT Southwestern Medical Center have identified a specific gene, Meis1 that regulates the heart’s ability to regenerate after injuries. The original article can be found in Nature.

The MMRRC has a GENSAT mouse containing multiple copies of a modified BAC in which EGFP reporter gene is inserted immediately upstream of the Meis1 coding sequence of the targeted gene.

MMRRC Resuscitation Success Rate

In 2012, the MMRRC was able to successfully deliver 246 out of 247 resuscitation orders. Please consider our services to best meet your research needs.

MMRRC iPod Raffle Winner: Caius G. Radu, M.D. - UCLA

In an effort to determine MMRRC's contribution to biomedical research, we reached out to all our previous customers and asked for additional information on previous orders. Customers who filled out the raffle form with valid NIH Grant entries and/or Pubmed publication IDs were entered into a raffle with a chance to win a new iPod. The raffle winner was selected today. Congratulations to Dr. Caius G. Radu from University of California, Los Angeles for winning the iPod. We would like to thank all those who participated in this raffle and provided valuable information about their past purchases from MMRRC. We appreciate their time and effort.

Terry Magnuson elected to IOM 2012.

Our very own Terry R. Magnuson, Ph.D., Sarah Graham Kenan Professor and chair, department of genetics, and vice dean for research, School of Medicine, University of North Carolina, Chapel Hill, and Project Director for the MMRRC at North Carolina-Chapel Hill, was just elected to the Institute of Medicine of the National Academies.

New MMRRC released!

Welcome to the newly revised MMRRC website! The goal of this revision is to modernize the look and feel of MMRRC's web presence. We hope the new simplified search feature will make finding the products you are looking for easier. For any questions/problems you have regarding this release, please email us at service@mmrrc.org, or use the Feedback function to the right side of the page.