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Mouse lines generated by the MRC Genome Editing Mice for Medicine programme: a case study

Posted by , on 28 October 2022

By David Christensen

At the Mary Lyon Centre at MRC Harwell we have our 10th Genome Editing Mice for Medicine (GEMM) call open and accepting applications, so we decided it would be a good opportunity to look back at genetically altered mouse lines generated for successful applicants from previous funding calls. We have created some case studies that demonstrate the range of work we have supported and highlight some of the lines that we have available for the scientific community

The GEMM programme offers the expertise and resources required to deliver and validate new and innovative mouse models that contribute to answering vital, pertinent scientific and clinical questions that can only be answered by the use of an in vivo model. Successful applicants demonstrating the scientific and clinical importance of their desired model have their novel mouse line designed and produced free of charge and made available to the scientific community. The first call for applications was made in 2016 and, so far, more than 80 novel genetically altered mouse lines have been generated.

One example line is C57BL/6NTac-Gldcem1H/H, which contains a disease-associated point mutation created by CRISPR/Cas9 in the gene GLDC.

Glycine decarboxylase (GLDC) is one of four enzymes that make up the glycine cleavage system (GCS), a complex that regulates the abundance of the amino acid and neurotransmitter glycine. This is done by catabolising glycine to release carbon dioxide and transfer a one-carbon unit into mitochondrial folate one-carbon metabolism. Mutations in GLDC have been found in patients with a severe inherited metabolic disease, Non-Ketotic Hyperglycinemia (NKH) and neural tube defects (NTDs). GLDC has also been found to be highly expressed in some cancers and it’s thought that sensitivity to GCS inhibition might provide a therapeutic strategy. Triplication of GLDC has been seen in bipolar/schizoaffective disorder, likely due to low levels of glycine impacting its role as a neurotransmitter.

NKH is a rare, life-limiting inherited metabolic disease characterised by accumulation of excess glycine in the body fluids and tissues. It becomes apparent soon after birth with lethargy, breathing difficulties, and neurological symptoms, including seizures. Affected individuals suffer epilepsy and profound delay in development. More than 80% of patients with NKH carry mutations in GLDC. NTDs are severe birth defects of the developing nervous system that affect 1 in 1,000 pregnancies worldwide. Due to the importance of folate for brain development, disruption of folate metabolism is implicated in causing NTDs and folic acid supplements can prevent some, but not all NTDs. The GLDC missense mutation S951Y has been identified both in patients with NKH and with NTDs.

To provide a pre-clinical model for these diseases, Nick Greene, a group leader at the UCL Great Ormond Street Institute of Child Health, applied to the GEMM programme to generate a mouse model for the S951Y variant (S956Y in mice). He and his team were then able to generate mice carrying the S956Y variant in combination with a deleted copy of GLDC, as a means to genetically copy the combination of variants present in an NKH patient. Using this model, they were recently able to show mild but significant elevation of plasma glycine, suggesting that the mutant protein retains some function, when compared with the glycine elevation seen in a knockout model. Despite only mild elevation of plasma glycine, there was still significant glycine accumulation in the brain, as well as a trend towards accumulation of related compounds that are also thought to cause epilepsy. Importantly, they were also able to demonstrate that glycine levels in the brain could be normalised by activation of glycine conjugation via administration of cinnamate, which could suggest a future therapy.

Prof Greene’s team plan to use the model to test disease treatments, including via gene therapy, and the model could also be useful for testing of putative genetic interactions with “second hit” variants that may increase the likelihood of NTDs.

This line and all others generated through the GEMM programme are available through the National Mouse Archive, here at MRC Harwell, and through the European Mouse Mutant Archive (EMMA).

We are currently accepting applications for the 10th GEMM call and invite you to nominate ideas and designs for your own genetically altered mouse lines.

Application Deadline: 2nd December 2022

Find out more and apply!

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Protocols for data visualization

Posted by , on 27 October 2022

Scientists are familiar with protocols that describe in a step-by-step fashion how an experiment is performed. But they are usually less familiar with code or scripts for handling data. Yet, experimental protocols and computer instructions have a similar structure and purpose. Therefore, it should be within reach for experimental scientists to add coding skills to their toolkit. This is a very valuable skill to have as it enables automated, reproducible data processing and visualization. To lower the barrier for using R and the ggplot2 package for data visualization, I have written a book that is available online: https://joachimgoedhart.github.io/DataViz-protocols/

In my opinion, the best part of the book is the section with full, dedicated dataViz protocols. Examples of the output of three protocols is shown below. The protocols use realistic experimental data and provide step-by-step instructions that readers can reproduce or repurpose for their own use.

The book is work in progress, so this is not a final version as it will be updated. Especially the chapter with dataViz protocols will be extended. I will announce the addition of new protocols on twitter. I hope that the book is useful and that it provides a solid foundation for anyone that wants to use R for the analysis and visualization of scientific data that comes from a wetlab. I look forward to seeing the results on twitter (and please tag me: @joachimgoedhart), in meetings, in preprints or in peer reviewed publications.

Looking back

Previously, I have authored a number of blogs on the Node that provide step-by-step instructions on how to do data wrangling or plotting in R. The first blog was about the conversion of ‘spreadsheet’ type data into tidy data. I wrote this blog because I had a hard time understanding the tidy format. Blogging about it helped me to understand the concept and I thought it would also serve others who want to learn R. I continued to post step-by-step guides whenever I figured out something new (to me) and the enthusiastic responses from colleagues were very rewarding.
At that time, however, I lacked an important skill which is called ‘literate programming’. This approach to programming combines styled text with chunks of code. It is a great way to explain and show what code is doing in a step-by-step way. After I learned literate programming in R with Rmarkdown, I decided to convert the blogs into this format. From there on, it was a logical step to compile the different topics into a book.

Looking forward

The advantage of Rmarkdown as the framework is that it is easy to maintain, edit and update. Using Rmarkdown, new protocols can be written independently and added to the book as individual chapters. At this moment, there are 12 complete protocols and I’m preparing another 8. I take inspiration from nice data visualizations that I see and I also do remakes of figures that we have published. If you have any ideas for a remake of a plot or if you have seen a nice dataViz which could use a protocol, please let me know! Also, I welcome any feedback on any aspect of the book.

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Development presents… modelling development in vitro – videos

Posted by , on 26 October 2022

On Tuesday 11 October, Development hosted three talks on the topic of our latest Special Issue, Modelling Development In Vitro.

Below you’ll find each of the talks and Q&As hosted by our Associate Editor, Matthias Lutolf (EPFL).

Alexandra Wehmeyer (M.D. thesis studentand Sebastian Arnold (Acting Director, Institute of Pharmacology, University of Freiburg)
‘Chimeric 3D-gastruloids – a versatile tool for studies of mammalian peri-gastrulation development’

You can read the Research Article here.

Ansley Conchola (MSTP MD/PhD candidate in Jason Spence‘s lab at the University of Michigan Medical School)
‘Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types’

You can read the full Research Article here.

Sham Tlili (CNRS research investigator at the Marseille Developmental Biology Institute (IBDM) in Aix-Marseille University)
‘A microfluidic platform to investigate the role of mechanical constraints on tissue reorganization’

You can read the Research Article here.

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Developing news

Posted by , on 25 October 2022

This week, #SciTwitter has been focussed on discussions around publishing, starting with prestige-signalling, followed by a big announcement from eLife, which received mixed reactions on Twitter. Going forward, eLife will no longer be accept or reject papers after review, but will publish a version of record (VOR) alongside public peer reviews. Check out their announcement for more details. We’ve picked out some tweets on both topics, and as always, click on the tweet for the full discussion and the opportunity to fall into a Twitter rabbit hole!

Prestige-signalling

eLife announcement

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The 2nd Crick-Beddington Developmental Biology Symposium: Meeting Summary

Posted by , on 20 October 2022

The 2nd Crick-Beddington Developmental Biology Symposium took place at The Francis Crick Institute between 9-10 October 2022. The hybrid symposium was generously funded by the MRC Rosa Beddington fund, which was established to uphold her memory and support curiosity-led science. Although a little later than originally planned, the conference maintained a similar ethos to the 1st symposium in 2019 (see an overview of that meeting from Alex Gould and Vicki Metzis and my previous Meeting Summary); many of the plenary speakers had direct links to Rosa and the talk topics reflected Rosa Beddington’s love of embryos and microscopy, as well as her meticulous description of morphogenesis. Shankar Srivivas, a former postdoc with Rosa and co-organiser of the meeting, opened the symposium with memories and photos of Rosa, mentioning her work on transplanting the mouse node (Beddington, 1994), how she believed in unity between all model organisms and how she often felt more comfortable behind the camera than in front of it.

A photo of Shankar Srinivas (organiser)  by sharing some photos of Rosa Beddington.
Shankar Srinivas (organiser) begins the symposium by sharing some memories and photos of Rosa Beddington.

Patrick Tam (University of Sydney) began the meeting by discussing how he and Rosa had a common interest in mouse gastrulation and were each other’s first collaborators in the late 1970s. Patrick presented a spatial transcriptomic atlas of the gastrula mouse embryo that provides insights into the molecular activity underpinning lineage trajectory during gastrulation. Matthew Stower (Srinivas lab, University of Oxford) also discussed mouse gastrulation, using light-sheet imaging to reveal coordinated, collective migratory behaviours in the dorsal visceral endoderm. In their first talk as an independent group leader, Diana Pinheiro (Research Institute of Molecular Pathology) employs computational modelling to understand the collective internalisation of the mesendoderm in response to morphogen signalling during zebrafish gastrulation. Yanlan Mao (University College London) also uses computational modelling to understand how mechanics generates the three major folds in the Drosophila wing disc and how structures are maintained under stress, such as when larvae are constricted. On this theme of mechanics and morphogenesis, Caren Norden (Gulbenkian Science) discussed optic cup development, revealing the importance of the extracellular matrix for the migration of a population of ‘rim cells’ into the retinal neuroepithelium and Toby Andrews (Priya lab, Crick) zebrafish heart morphogenesis and the role of mechanical stretching for trabecular development. Similarly, Golnar Kolahgar (University of Cambridge) explained how vinculin-dependent mechanosensory activity in Drosophila enterocyte progenitors maintains homeostasis of the intestine. Irene Miguel-Aliaga (MRC London Institute of Medical Sciences) presented a different perspective on the Drosophila gut, discussing how inter-organ communication creates sex differences in intestine geometry and function, revealed using microCT. Simon Bullock (MRC Laboratory of Molecular Cell Biology), a former graduate student with Rosa Beddington, uses Drosophila as a model to understand how dynactin-dynein complexes asymmetrically localise RNA transcripts, including Gap genes. Drosophila segmentation was the focus of Jacques Bothma‘s talk (Hubrecht Institute) as well. Jacques has developed ‘LlamaTags’ for rapid imaging of transcriptional dynamics to reveal how the genome encodes and interprets time. Alain Chédotal (Vision Institute) similarly works on the leading edge of technology, employing virtual reality for the characterisation and 3D analysis of cleared human embryos. Jan Huisken (University of Göttingen) concluded the imaging theme by presenting Flamingo, a low-cost, customisable, modular light-sheet imaging microscopy set-up that can be shipped around the world and operated remotely.

The photo of outside of The Francis Crick Institute
The outside of The Francis Crick Institute.

Several of the talks reflected on metabolism. Josh Brickman (reNEW), a former postdoc with Rosa, looked back at their time together with humour, reflecting how Rosa had insisted he work on transcription factors, to which he now credits his career. Josh explained how transcription factor residence on enhancers supports plasticity in foregut stem cells and lipid metabolism alters gene expression via sirtuin-dependent acetylation. Aydan Bulut-Karslioglu (Max Planck Institute for Molecular Genetics) uses mTOR-inhibited embryonic stem cells as a model to show that fatty acid degradation sustains mammalian diapause. Moving from development to cancer, Salvador Aznar-Benitah (Institute for Research in Biomedicine) discussed how metastasis-initiating cells have high fatty acid metabolism and are sensitive to dietary fats, such as palmitic acid. Meritxell Huch also showed how lipid metabolism can reprogram differentiated liver tumour cells and discussed the importance of TET1-mediated demethylation for de-differentiation during liver regeneration. Selin Jessa (Kleinman lab, McGill University) presented the developmental origins of paediatric gliomas, focusing on the links between histone 3 lysine 27 methylation mutations and 3′ Hox genes.

Another emergent theme from the meeting was developmental principles across scales. At the population level, Hugh Ford (Chubb lab, Laboratory for Molecular Cell Biology) uses Dictyostelium to study cAMP signal propagation and cell migration. In tissues, Danelle Davenport (Princeton University) explained how the periodic pattern of skin appendages is established via polarising morphogenesis and Jakub Sumbal (Koledová lab, Masaryk University) presented insights from single-cell RNA-sequencing data of terminal end buds during mammary gland epithelial branching. Val Wilson (University of Edinburgh), a former postdoc in Rosa’s lab, presented research on two populations of axial progenitors in mice (neuromesodermal progenitors and lateral-paraxial mesodermal progenitors) and how signalling controls fate decisions within these populations. At the cellular level, Tamara Caspary (Emory School of Medicine) began her talk by explaining how Kathryn Anderson and Rosa Beddington catalysed her research in mouse ‘hat’ gene mutations, which were later mapped to ciliogenesis and Hedgehog signalling. Tamara showed how these two processes could be uncoupled through the activity of ARL13B in the cilia versus the cytoplasm. Rita Sousa-Nunes (King’s College London), a graduate student with Rosa, similarly aims to uncouple the proteome and transcriptome. Rita began her talk by sharing how Rosa once said to her “if she did it all again she’d [work on] flies and she’d [work with] with Daniel St Johnston”. Using Drosophila neural stem cells as a model, Rita explained how quiescent cells retain untranslated transcripts in their nuclei. Finally, Alex Schier (University of Basal) reminisced about how he once sat next to Rosa before she gave a talk, remarking to him, “I hope I don’t faint”. Alex presented on how the cell develops a specialised form and function by expressing gene ‘modules’, using the differentiation of zebrafish notochord and hatching gland as a model system.

Tamara Caspary presenting a photo of Rosa Beddington and Kathryn Anderson (1952-2020).
Tamara Caspary told the story about her work was catalysed by the motivation of Rosa Beddington and Kathryn Anderson (1952-2020).

A new addition to this year’s programme was two sessions of flash talks by a selection of the poster presenters. Equipped with just three minutes each, the flash presenters covered a wide range of different topics within developmental biology. They did a fantastic job of enticing the audience to visit their poster during the breaks and poster sessions. Several speakers use live cell imaging to answer their development questions: Sunandan Dhar (Saunders lab, National University of Singapore) studies cell fusion in skeletal muscle; Jean-Francois Derrigand (Spagnoli lab, King’s College London) is exploring exocrine pancreas morphogenesis; Michael Smutny (University of Warwick) is investigating global tissue reshaping zebrafish gastrulation; Markus Schliffka (Maitre lab, Curie Institute) studies the fluid dynamics of microlumens that form in the mammalian blastocyst; and Cerys Manning (University of Manchester) follows dynamic decisions in the development of the eye. Also studying eye development, Jana Sipkova (Franze lab, University of Cambridge) investigates the role of Eph/Ephrin signalling and mechanics in neuronal migration between the eye and the optic tectum. Making the link between mechanics and development, Eirin Maniou (Galea lab, University College London) uses 3D printing to measure mechanical forces during chick neural tube closure in vivo and Sera Weevers (Tsiairis lab, Friedrich Miescher Institute for Biomedical Research) studies how osmosis-driven mechanical stretching underlies the establishment of the Wnt organiser in Hydra. Further understanding the connections between signalling, transcriptional regulation and cell fate, Sergio Menchero (Tuner lab, Crick) aims to uncouple transcriptional and morphological changes by comparing opossum and mouse organogenesis. Similarly, Joaquina Delas (Briscoe lab, Crick) studies how cell fate decisions in the neural tube are regulated at the chromatin level by differential binding and differential element availability and Vicki Metzis (Imperial Collge London) investigates how the posterior neural fate is acquired via CDX2. Furthermore, Lisa Thomann (Lemaire lab, CRBM) uncovers the role of PI3K signalling in ascidian notochord development. Finally, at the subcellular level, Azelle Hawdon (Zenker lab, Australian Regenerative Medicine Institute) studies sub-cellular mRNA asymmetry in mammalian embryogenesis and Chantal Roubinet (Baum lab, University College London) spoke on the asymmetric inheritance of nuclei during Drosophila neuroblast divisions.

As well as the plenaries, selected talks and flash talks, there were also presentations from ThermoFisher and 10X Genomics. For ThermoFisher, Sarawuth Wantha presented the Amira software, suitable for large lattice light-sheet microscopy data, transmission electron microscopy, AI-based segmentation and high-content screening. On behalf of 10X Genomics, Nicola Cahill introduced the Chromium, Visium and Xenium platforms for single-cell sequencing, spatial transcriptome and in situ applications, respectively.

A final variation from the first meeting was the hybrid aspect. I was fortunate to attend most of the meeting in person; however, I didn’t miss out by having to duck out a little early to catch my train. I was able to quickly log in to the live stream on Zoom to watch the concluding remarks. I hope those of attended virtually also found the hybrid format helped accessibility. The switching, too, between in-person and video presenters was seamless and it was great that those who could not attend in person were still able to share their work with us.

A screenshot from zoom showing concluding remarks from Nic Tapon (organiser) sharing some of Rosa's paintings of Mendel.
Concluding remarks from Nic Tapon (organiser) sharing some of Rosa’s paintings of Mendel, appropriate because this year marked the 200th anniversary of his birth.

Nic Tapon concluded the symposium by thanking the speakers, the Crick Events team, sponsors and co-organisers; Shankar Srinivas, Alex Gould and Caroline Hill. Nic explained how two of Rosa’s paintings of Mendel that hang in the Crick were especially appropriate this year because it’s the 200th anniversary of Mendel’s birth.

Thank you to the organisers for their effort in assembling the symposium together, chairing sessions and for the smooth execution of the programme. I also thank all the speakers for sharing their stories, both of their science and their memories of Rosa Beddington.

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Genetics Unzipped: Past to present – Searching for evolutionary stories in ancient DNA

Posted by , on 20 October 2022

Neanderthal skull against a black background

Where did we come from? And how are we related to the ancient species that came before us? Asking questions like these is part of what makes us human. But, genetically speaking, what really does make us human?

Dr Kat Arney

In the latest episode of the Genetics Unzipped podcast, we’re exploring what we can discover about our evolution from our DNA, and what evolutionary secrets might be contained in the ancient DNA of our ancestors. Dr Kat Arney looks at why this year’s Nobel Prize awarded for the genomics of ancient humans, how genetic mutations allow Tibetans and their dogs to survive in high altitudes, and dispelling the myth about why many adults can drink milk.

Genetics Unzipped is the podcast from The Genetics Society. Full transcript, links and references available online at GeneticsUnzipped.com.

Subscribe from Apple podcasts, Spotify, or wherever you get your podcasts.

Head over to GeneticsUnzipped.com to catch up on our extensive back catalogue.

If you enjoy the show, please do rate and review on Apple podcasts and help to spread the word on social media. And you can always send feedback and suggestions for future episodes and guests to podcast@geneticsunzipped.com Follow us on Twitter – @geneticsunzip

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Development presents… From Stem Cells to Human Development – videos

Posted by , on 19 October 2022

On Monday 12 September, we livestreamed a session from our meeting ‘From Stem Cells to Human Development’, as part of our Development presents… webinar series.

Below you can find the recordings of the talks from Sarah Teichmann and Sergiu Pasca, as well the panel discussion featuring Amander Clark, Robin Lovell-Badge, Sergiu Pasca, Sarah Teichmann and Magdalena Zernicka-Goetz, chaired by Patrick Tam.

Sarah Teichmann (Wellcome Sanger Institute, UK)
‘Human development: one cell at a time’

Sergiu Pasca (Stanford University, USA)
‘From stem cells to assembloids: constructing and deconstructing human nervous system development and disease’

Panel discussion with Amander Clark, Robin Lovell-Badge, Sergiu Pasca, Sarah Teichmann and Magdalena Zernicka-Goetz
‘Technical, ethical and legal challenges of studying early human development’

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Postdoctoral Research Scientist in Cardiac Developmental Biology

Posted by , on 18 October 2022

Closing Date: 14 November 2022

Applications are invited for a Postdoctoral Research Scientist to join A/Prof Duncan Sparrow’s laboratory at the University of Oxford to work on a project using mouse models to investigate environmental influences on embryonic heart development that may lead to congenital heart disease in humans. This is a 5 year position fully funded by the British Heart Foundation. Applications are particularly welcome from women, black and minority ethnic candidates who are under-represented in academic posts in Oxford. https://tinyurl.com/bdd5raa7

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Developing news

Posted by , on 18 October 2022

Twitter has felt a little quieter on the #devbio front these past two weeks, perhaps in anticipation of the long awaited #ISDB2021, which kicked off this Sunday. If you have not made it to the meeting this time, you can still follow along using the hashtag #ISDB2021. We have also pick a few other tweets with interesting discussions that caught our eyes, as well as bringing you the preLights related to developmental and stem cell biology.

In vitro, in vivo or both, and does it matter?

No time for Twitter?

Boosting your mental health

Important teaching points!

Getting organised, continued

preLights in #devbio

Cellular Crosstalk: How Rnf20 communicates across cell types during cardiac development

How “nuclear massaging” helps dendritic cells find their way home: Alraies and colleagues present a cell shape sensing axis that guides dendritic cells to lymph nodes.

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Behind the paper: Characterising the spatiotemporal dynamics of microglia across the human lifespan

Posted by , on 17 October 2022

Dr David A. Menassa and Professor Diego Gomez-Nicola at the University of Southampton, UK recently published an article in Developmental Cell where they reveal how the microglial population colonises the human frontal cortex. Dr Menassa gave us a behind the scenes look at how the story came together.

  • How did you get started on this project?

I joined the Gomez-Nicola lab in October 2017 as a research fellow. The funding had been granted by the Leverhulme Trust prior to my arrival, and all was in place to set the human lifespan study in motion.

The task of securing healthy human tissues from whole embryos to advanced ageing was a challenging one. It took several years to establish the tissue collection and 12 tissue resources within the UK and abroad were consulted. There was a substantial administrative load. Human tissue work in general is fraught with challenges: even when one acquires the tissues, there are no guarantees that the antigenic targets will have been preserved. The assumption is that they should be, but there are many factors that come into play making work with human tissues a good exercise in patience, focus and resilience. Once the frustrations were out of the way, the project kicked off at full speed. I was lucky to be part of a very supportive laboratory environment, working alongside a team of intramural and extramural collaborators. This paper is evidence of great teamwork and we are delighted to be able to share our findings with the scientific community.

  • What was already known about the developmental dynamics of microglia in the human brain prior to your work?

Two studies on adult human tissues (including one from the Gomez-Nicola lab) were published in 2017 showing that microglial turnover in humans is much faster than previously thought and that the entire population is renewed several times during a lifetime [2, 3]. Additionally, microglial proliferative dynamics increase during pathology and have been the target of therapies to limit proliferation in neurodegenerative disease particularly Alzheimer’s disease models [4]. Very little was known about microglial dynamics during the critical stages of human brain development and the early postnatal age, and this was largely due to the limited availability of tissues for research.

In the latter half of 2020, two papers profiled microglial developmental states during early embryonic and early fetal lives in humans [5, 6]. These studies showed that ontogenic pathways were conserved between mice and humans and that microglia became immunocompetent from as early as the 11th week of gestation. In 2022, the regional microglial transcriptome was described in humans between 8-23 weeks of gestation: this was the first study to look at specific anatomical regions such as the cortex and the cerebellum [7]. Altogether, these studies offered an important view of specific temporal windows during development. In our study, we covered the entire human lifespan, detailing the spatiotemporal dynamics of microglia from the moment these cells arrive to the human developing brain at 4 pcw up until they turnover very slowly in adult life. We profiled these cells in all layers of the cortex in the frontal lobe, the brain region responsible for higher order cognitive and executive function in humans.

  • Can you summarise your findings?

There are four important temporal windows during human brain development when we see microglial changes: the first one is when microglia arrive to the brain with the onset of circulation at 4 pcw; the second is at the transition between embryonic to fetal life at 9-10 pcw; the third is at 13-14 pcw and the fourth is during early childhood between 0.5-1 year of age. Microglial expansion in the brain is via a wave-like pattern of cycles of migration and proliferation, increasing cell number, which is further refined by selective cell-death. The changes in microglial dynamics are aligned with co-occurring neurodevelopmental processes. We found no sex differences during these developmental stages. In adult life, the population self-renews at a relatively steady rate until advanced ageing. This pattern of colonisation is unique to humans and is strikingly different than what we see in mouse.

Figure 1 Microglial dynamics across the human lifespan. This graphical abstract was modified from [1] and shows the proliferation, cell number and cell death changes of microglia between 3 postconceptional weeks and 75 years of life. The arrows represent ongoing processes.
  • When doing the research, did you have any particular result or eureka moment that has stuck with you?

Seeing the first fully labelled embryo for microglia, other tissue-resident macrophages and proliferative cells in the brain matter, liver, spleen, spinal cord, and heart all visible in one slide was a special moment. I remember sending Dr Gomez-Nicola the first image and we were both excited and thrilled that it was all worth the wait; the signal was very clear and from that point onwards, we were confident that the project was heading in the right direction. The second moment was when we had all the data unblinded and plotted across the lifespan for all tissues: it was a roadmap, and we could see the exact pattern that microglia followed prenatally and postnatally.

  • And what about the flipside? Any moment of frustration or despair?

Human tissue research is challenging, but the end-result is very rewarding. In this paper, we could not obtain samples with consent for research use from late childhood and adolescence. Therefore, we are missing part of the whole picture. As the pattern of growth and myelination of the frontal lobe is unique in humans during these stages, it will be interesting to see what happens to microglial dynamics.

  • Where will this story take you next?

Now that we know the temporal windows of relevance in microglial dynamics, the next step is to begin dissecting how microglial cells interact with the neurodevelopmental environment. This could be by elucidating the cues that these cells get from the brain at each step and in this way, we can start identifying why the population behaves the way it does. This is important as microglia are part of the neuropathology of neurodevelopmental disorders. To find out how these cells contribute to normal and altered neurodevelopment, we need to dissect the signalling pathways between them and developing neurons.

  • What is next for you after this paper?

I am currently stipendiary lecturer of neurophysiology and neuroscience at the Queen’s College, University of Oxford and visiting researcher in neurodevelopment at the Croatian Institute for Brain Research, University of Zagreb. I am continuing my research on microglial development and how this relates to neurodevelopmental disorders. I am applying for tenured positions in the UK and Europe to set up my own research group.

Bibliography

1.       Menassa, D.A., et al., The spatiotemporal dynamics of microglia across the human lifespan. Dev Cell, 2022.

2.       Askew, K., et al., Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. Cell Rep, 2017. 18(2): p. 391-405.

3.       Réu, P., et al., The Lifespan and Turnover of Microglia in the Human Brain. Cell Rep, 2017. 20(4): p. 779-784.

4.       Olmos-Alonso, A., et al., Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain, 2016. 139(Pt 3): p. 891-907.

5.       Bian, Z., et al., Deciphering human macrophage development at single-cell resolution. Nature, 2020. 582(7813): p. 571-576.

6.       Kracht, L., et al., Human fetal microglia acquire homeostatic immune-sensing properties early in development. Science, 2020. 369(6503): p. 530-537.

7.       Li, Y., et al., Decoding the temporal and regional specification of microglia in the developing human brain. Cell Stem Cell, 2022. 29(4): p. 620-634.e6.

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