LHX6, MTG8 and MTG16: functions and interactions in cortical interneuron development
Lead Research Organisation:
University College London
Department Name: The Wolfson Inst for Biomedical Research
Abstract
Inhibitory interneurons play pivotal roles within the cortex, the seat of higher order information processing in mammals. Defects in cortical interneurons cause neural network imbalance and can lead to seizure-based and neurodevelopmental cognitive and psychiatric impairments such as autism and schizophrenia. Genetic mutations affecting interneuron maturation and leading to cognitive dysfunction have been identified but we are far from understanding the genetic complexity of cortical interneuron development and how genetic defects can lead to disorders.
There is a large diversity of interneurons in the cortex and it is largely unknown how this diversity is established in the developing embryo. We discovered two novel genes, Mtg8 and Mtg16, that function in concert with the master regulator of cortical interneuron development Lhx6 in the determination of interneuron subtypes in animal models. We aim to understand the relationship between the three genes and their specific requirements for interneuron development in the embryo. We will also examine wider genetic programs that are triggered by the action of these proteins in order to gain further insight into the genetic makeup that dictates interneuron cell identity. Ultimately, this knowledge will be invaluable not only in understanding interneuron-based developmental disorders, but also in the generation of interneurons from stem cells for use in transplantation repair therapies -a route already adopted experimentally for epileptic conditions in animal models.
There is a large diversity of interneurons in the cortex and it is largely unknown how this diversity is established in the developing embryo. We discovered two novel genes, Mtg8 and Mtg16, that function in concert with the master regulator of cortical interneuron development Lhx6 in the determination of interneuron subtypes in animal models. We aim to understand the relationship between the three genes and their specific requirements for interneuron development in the embryo. We will also examine wider genetic programs that are triggered by the action of these proteins in order to gain further insight into the genetic makeup that dictates interneuron cell identity. Ultimately, this knowledge will be invaluable not only in understanding interneuron-based developmental disorders, but also in the generation of interneurons from stem cells for use in transplantation repair therapies -a route already adopted experimentally for epileptic conditions in animal models.
Technical Summary
Inhibitory interneurons form essential elements of cortical circuits. There are several distinct subtypes of interneurons in the mature cortex; they play different roles in network function and have distinct origins in the embryonic telencephalic neuroepithelium. The molecular mechanisms of interneuron subtype specification are largely unknown. We identified two novel transcriptional regulators, MTG8 and MTG16, that are enriched in interneurons expressing the master regulator of cortical interneuron development LHX6. Our pilot data demonstrate a requirement for MTG factors in LHX6-dependent cortical interneuron specification pathways. We hypothesize that the MTG proteins act in the same genetic pathway(s) as LHX6, and we propose a series of experiments to determine the nature of their interaction as well as their specific and common functions in interneuron lineages. We will use a combination of genetic approaches in vivo and biochemical approaches in vitro. The work will significantly advance our understanding of the genetics of interneuron development and will have far reaching impact on neurodevelopmental disease research and stem cell therapies.
Planned Impact
The proposed work will elucidate the role of the transcriptional regulators MTG8 and MTG16 in cortical interneuron development and their interplay with the master regulator of cortical interneuron development LHX6. Given the importance of inhibitory interneurons in cortical processing and neurodevelopmental or other seizure-based disorders, the research will benefit several branches of academic and translational research.
1. There will be immediate benefits to the interneuron development academic research field as the work will provide further insight into the specification and differentiation of cortical interneurons and the molecular drivers behind these processes.
2. There will be immediate benefits to the stem cell research community where embryonic and induced pluripotent stem cells are being used for the derivation of cortical interneurons in culture as the work will elucidate the role of the LHX6 and MTG transcriptional regulators in cortical interneuron development and potential pathways for driving stem cells into specific fates.
3. In the longer term, knowledge into the molecular specification of cortical interneurons and the role of the LHX6 and MTG proteins will allow the development of cortical interneuron subtypes in culture and the use of these in effective transplantation therapies for conditions such as epilepsy where cortical inhibition is impaired. This approach has already been applied experimentally and shown to be effective even with mixed populations of interneuron subtypes. Knowledge into the transcriptional regulation of cortical interneuron development will allow a refinement of this approach for more effective transplantation therapies. Therefore the research has the potential to contribute to the nation's health.
4. Interneurons have been implicated in neurodevelopmental diseases such as autism, schizophrenia and intellectual disability. Emerging opinions suggest commonalities in the genetic basis of these disorders. Mutations in MTG8 have been found in humans with intellectual disability suggesting a role in this disorder. Our finding of defective interneuron development in mice lacking MTG8 may provide a clue into the cognitive phenotype in humans. In the longer term, the work proposed will benefit the neurodevelopmental disease field and thus contribute to the nation's health through understanding of some of the genetic basis of interneuron-based diseases and potentially the development of effective therapies.
5. Staff working on the project will benefit by expanding and enriching their research skills through bench work and enhancing their professional skills through oral and written presentations, scientific networking and collaboration as well as public engagement when the opportunity arises. These are transferable skills highly sought after by non-academic employers. Through publications and collaborations the work will enhance the national and international profile of our Universities.
6. Public beneficiaries can vary. Immediate beneficiaries include secondary schoolchildren who may join the lab for work experience. This will provide them with a glimpse of academic research in basic science. The wider public will benefit in the long term through the availability of more effective therapies developed using knowledge gained in this project.
1. There will be immediate benefits to the interneuron development academic research field as the work will provide further insight into the specification and differentiation of cortical interneurons and the molecular drivers behind these processes.
2. There will be immediate benefits to the stem cell research community where embryonic and induced pluripotent stem cells are being used for the derivation of cortical interneurons in culture as the work will elucidate the role of the LHX6 and MTG transcriptional regulators in cortical interneuron development and potential pathways for driving stem cells into specific fates.
3. In the longer term, knowledge into the molecular specification of cortical interneurons and the role of the LHX6 and MTG proteins will allow the development of cortical interneuron subtypes in culture and the use of these in effective transplantation therapies for conditions such as epilepsy where cortical inhibition is impaired. This approach has already been applied experimentally and shown to be effective even with mixed populations of interneuron subtypes. Knowledge into the transcriptional regulation of cortical interneuron development will allow a refinement of this approach for more effective transplantation therapies. Therefore the research has the potential to contribute to the nation's health.
4. Interneurons have been implicated in neurodevelopmental diseases such as autism, schizophrenia and intellectual disability. Emerging opinions suggest commonalities in the genetic basis of these disorders. Mutations in MTG8 have been found in humans with intellectual disability suggesting a role in this disorder. Our finding of defective interneuron development in mice lacking MTG8 may provide a clue into the cognitive phenotype in humans. In the longer term, the work proposed will benefit the neurodevelopmental disease field and thus contribute to the nation's health through understanding of some of the genetic basis of interneuron-based diseases and potentially the development of effective therapies.
5. Staff working on the project will benefit by expanding and enriching their research skills through bench work and enhancing their professional skills through oral and written presentations, scientific networking and collaboration as well as public engagement when the opportunity arises. These are transferable skills highly sought after by non-academic employers. Through publications and collaborations the work will enhance the national and international profile of our Universities.
6. Public beneficiaries can vary. Immediate beneficiaries include secondary schoolchildren who may join the lab for work experience. This will provide them with a glimpse of academic research in basic science. The wider public will benefit in the long term through the availability of more effective therapies developed using knowledge gained in this project.
Organisations
- University College London (Lead Research Organisation)
- Institute of Biology (IBENS) (Collaboration)
- University College London (Collaboration)
- University of Liege (Collaboration)
- Kanazawa University (Collaboration)
- Free University of Brussels (Collaboration)
- Medical Research Council (MRC) (Collaboration)
People |
ORCID iD |
Nicoletta Kessaris (Principal Investigator) |
Publications
Tata M
(2016)
Regulation of embryonic neurogenesis by germinal zone vasculature.
in Proceedings of the National Academy of Sciences of the United States of America
Magno L
(2017)
NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory.
in Cell reports
Mieda M
(2017)
Fine-Tuning Circadian Rhythms: The Importance of Bmal1 Expression in the Ventral Forebrain.
in Frontiers in neuroscience
Harris KD
(2018)
Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.
in PLoS biology
Tinterri A
(2018)
Tangential migration of corridor guidepost neurons contributes to anxiety circuits.
in The Journal of comparative neurology
Silva CG
(2018)
Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis.
in Cell
Boon J
(2019)
Long-range projections from sparse populations of GABAergic neurons in murine subplate.
in The Journal of comparative neurology
Asgarian Z
(2019)
Hippocampal CA1 Somatostatin Interneurons Originate in the Embryonic MGE/POA.
in Stem cell reports
Magno L
(2021)
Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior.
in Cell reports
Kessaris N
(2022)
Human cortical interneuron development unraveled.
in Science (New York, N.Y.)
Description | Cortical interneurons are fundamental elements of the functioning brain. Failure of these neurons results in conditions such as epilepsy. Treatments using as stem cell or healthy interneuron transplantation into the diseased brain are being developed. Understanding how cortical interneurons are generated in the animal is essential for generating these cells from stem cells in the dish. We have identified a pair of novel regulators of the development of cortical interneurons. We have identified t |
Exploitation Route | Understanding the role of MTG8 and MTG16 in cortical interneuron development contributes to our understanding of human disease and the development of stem cell therapies. |
Sectors | Healthcare |
Title | MTG8 interacts with LHX6 to specify cortical interneuron subtype identity. |
Description | Cortical interneurons originating in the embryonic medial ganglionic eminence (MGE) diverge into a range of different subtypes found in the adult mouse cerebral cortex. The mechanisms underlying this divergence and the timing when subtype identity is set up remain unclear. We identify the highly conserved transcriptional co-factor MTG8 as being pivotal in the development of a large subset of MGE cortical interneurons that co-expresses Somatostatin (SST) and Neuropeptide Y (NPY). MTG8 interacts with the pan-MGE transcription factor LHX6 and together the two factors are sufficient to promote expression of critical cortical interneuron subtype identity genes. The SST-NPY cortical interneuron fate is initiated early, well before interneurons migrate into the cortex, demonstrating an early onset specification program. Our findings suggest that transcriptional co-factors and modifiers of generic lineage specification programs may hold the key to the emergence of cortical interneuron heterogeneity from the embryonic telencephalic germinal zones. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | N/A |
URL | https://crick.figshare.com/articles/journal_contribution/MTG8_interacts_with_LHX6_to_specify_cortica... |
Title | Transcriptomic analysis of CA1 inhibitory interneurons |
Description | Here you find transcriptomic data of CA1 GABAergic neurons, together with analysis results described in the paper "Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics" by Kenneth D. Harris, Hannah Hochgerner, Nathan G. Skene, Lorenza Magno, Linda Katona, Carolina Bengtsson Gonzales, Peter Lonnerberg, Peter Somogyi, Nicoletta Kessaris, Sten Linnarsson, and Jens Hjerling-Leffler (https://www.biorxiv.org/content/early/2018/04/18/143354) The file CA1Interneurons.mat contains all data in a MATLAB structure; a suite of MATLAB functions for plotting and processing this data can be found at https://github.com/cortex-lab/Transcriptomics. The remaining files contain the same data in tab separated text format. The file expression.tsv contains the UMI gene counts. Each column in the file corresponds to a cell. The first row contains the "cell name" - an actual name randomly assigned to each cell from a list of baby names released by the US census bureau. This name serves as a human-memorable unique identifier for each cell. Each row after that lists the expression of all genes in the cells, with the gene name in the first column. The file analysis_results.tsv contains the results of ProMMT cluster analysis, nbtSNE, and latent factor analysis (described in the manuscript) in a similar format. The file cell_metadata.tsv contains miscellaneous information from the sequencing pipeline again in the same format. The file latent_weights.tsv contains the gene weights coming from the latent factor analysis, in a similar format but now with a column for each gene that entered into this analysis (which is not all of them) For more files, including the raw sequencing data, please go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99888 For questions or correspondence please email kenneth.harris@ucl.ac.uk |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | N/A |
URL | https://figshare.com/articles/Transcriptomic_analysis_of_CA1_inhibitory_interneurons/6198656 |
Description | Blood vessels and neurogenesis |
Organisation | University College London |
Department | Institute of Ophthalmology UCL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided material for analysis |
Collaborator Contribution | The carried out the analysis |
Impact | PMID: 27821771 |
Start Year | 2016 |
Description | Circadian rhythms |
Organisation | Kanazawa University |
Country | Japan |
Sector | Academic/University |
PI Contribution | We provided research tools |
Collaborator Contribution | They carried out the work using some of our tools |
Impact | PMID: 28232786 |
Start Year | 2016 |
Description | Forebrain migration |
Organisation | Institute of Biology (IBENS) |
Country | France |
Sector | Academic/University |
PI Contribution | We provided tools for research |
Collaborator Contribution | They carried out the work using our tools |
Impact | PMID: 28921616 |
Start Year | 2016 |
Description | Interneuron migration |
Organisation | University of Liege |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We provided insight and tools for research |
Collaborator Contribution | They carried out the work using our tools |
Impact | PMID: 29474907 |
Start Year | 2016 |
Description | LHX and MTG proteins in cortical interneuron development |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We carry out the research project |
Collaborator Contribution | They provided materials for the project |
Impact | No outputs as yet |
Start Year | 2016 |
Description | MTG genes in the peripheral nervous system |
Organisation | Free University of Brussels |
Country | Belgium |
Sector | Academic/University |
PI Contribution | A collaboration has been initiated to look at the role of Mtg genes in peripheral nervous system development. We provide mice for this study. |
Collaborator Contribution | A student from the collaborating lab is in London using our mice. |
Impact | No outcomes yet. |
Start Year | 2022 |
Description | Pten in cancer and autism |
Organisation | University College London |
Department | UCL Cancer Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Obtained a collaborative grant from the Pten Foundation. Some of the work is carried out in my lab. |
Collaborator Contribution | Some of the work is carried out by the collaborators |
Impact | Grant awarded |
Start Year | 2016 |
Description | Science career talk at a school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | A brief introduction to science careers was followed by Q&A from final year A-level students. |
Year(s) Of Engagement Activity | 2022 |
Description | Science talk at a school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | A talk on @life as a research scientist' was presented at a secondary school. The children at the school were fully engaged and asked numerous questions. |
Year(s) Of Engagement Activity | 2019 |