The roles of non-coding and protein-coding genes in the evolutionary expansion of the cerebral cortex

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

The diversity of brain organizations is spectacular amongst vertebrates. The greatest variations are observed in the dorsal cortex and near its junction to other structures (at the pallial/subpallial boundary). Dorsal cortex of avian and reptilian brains contains only a component of the six layered isocortex of mammals. Although fundamental structures of the isocortex are similar in all mammals, there is a drastic increase in cortical size and complexity in mammals culminating with the human brain. Comparative developmental studies suggest that the elaboration of the mitotic compartments might have been the drive behind mammalian cortical evolution (Rakic, 1995; 2006; Kriegstein et al., 2006; Molnar et al., 2006a,b). The mechanisms and genes responsible for generating these variations can be understood by studying cortical development in various different species. This proposal examines two groups of genes. (1) The first group consists of protein coding genes which are known to be involved in cortical neurogenesis, formation of layers, radial and tangential migration of neurons. (2) The second assortment includes non-coding so-called 'macro-RNA' genes that exhibit distinct signatures of purifying selection, suggestive of functionality. Using the tools of modern genetics and comparative genomics we shall sequence and compare selected groups of genes from both categories and test their function in knockout mice and in in vitro and in vivo experimental paradigms. Through the study of these coding and non-coding genes, we wish to determine, in various taxa, the context in which the most common cortical development genes operate. Comparative aspects of cortical development not only point to evolutionarily relevant changes, but they also draw our attention to the limitations of some of the model systems currently used to understand human cortical developmental abnormalities and indeed reveal the mechanisms responsible for these abnormalities.

Technical Summary

The vertebrate cerebral cortex ranges from a 3-layered dorsal structure in reptiles and birds, to a gyrencephalic 6-layered structure in primates and other mammals. We hypothesize that slight differences in vertebrate developmental programs during evolution are responsible for the radial expansion contributing to increased lamination of the mammalian cortex and, later, for the tangential expansion of cortical surface area that ultimately produced the gyrencephalic cortex. Recent reports suggest that the origin and elaboration of the subventricular zone (SVZ) of cell division during vertebrate evolution facilitated this transition by increasing the pool of neural progenitors and prolonging the period of neurogenesis (Kriegstein et al., 2006; Molnar et al., 2006). These distinct mitotic compartments (VZ, SVZ / InternalSVZ and OuterSVZ in macaque) might enable unique and novel combinatorial effects from the available transcription factor pool. Given the high similarity between protein coding genomic regions in closely related organisms, subtle alterations within highly conserved noncoding genomic regions may have led to rapid and drastic alterations in brain formation. However, this claim remains unexplored as high quality genomic sequence and neuroanatomical analyses are available in very few species. By superimposing comparative genomic information that identifies brain-specific non-coding genes under purifying selection onto a neuroanatomical report of cortical neurogenesis in several different vertebrates, we seek to identify critical genetic and molecular factors involved in the formation of cerebral cortex with specific attention to the subventricular zone. From this template, we aim to isolate species or clade-specific brain development processes, associate these changes with alterations in particular genomic regions, and then use these observations as a foundation to reconstruct the evolution of the mammalian cerebral cortex.

Publications

10 25 50
 
Title Artworks generated by pupils and audience after neuroscience lectures 
Description https://history.medsci.ox.ac.uk/art/activities/brain-portraits/A resource for teaching Science, art and creativity Resource of new ideas to spark the imagination for teaching science through art with downloadable activities Nobel prize winning scientist, Sir Charles Scott Sherrington, was a neuroscientist who was passionate about teaching. He was an extraordinary man - a curious, creative scientist who expressed and explored his wonder at life through writing and poetry. Scientist-turne 
Type Of Art Artefact (including digital) 
Year Produced 2013 
Impact We received feedback on our website: https://history.medsci.ox.ac.uk/art/feedback/, indicating that the audience was engaged. 
URL https://history.medsci.ox.ac.uk/art/activities/brain-portraits/
 
Title The Oxford Science and Ideas Festival - The consciousness field 
Description https://www.dpag.ox.ac.uk/news/the-oxford-science-and-ideas-festival http://www.theconsciousnessfield.com/index.html Once again researchers from across our Oxford Neuroscience Community pulled all the stops out for the Oxford Science and Ideas Festival. Extensive programmes of activities were run by the Nuffield Department of Clinical Neurosciences and the Department of Experimental Psychology. In addition, the Department of Physiology, Anatomy and Genetics' Zoltan Molnar in collaboration with Colin Blakemore and St John's College put on a holographic presentation 'The Consciousness Field' created by artist Maria Lopez. 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2018 
Impact The exhibition was very well attended and the general public had the chance to ask questions from researchers and artists. http://www.theconsciousnessfield.com/index.html 
URL https://www.dpag.ox.ac.uk/news/the-oxford-science-and-ideas-festival
 
Description This BBSRC funded project on "the roles of non-coding and protein-coding genes in evolutionary expansion of the cerebral cortex" has been completed and numerous publications disseminated the results. The grant also lead for further funding (Prof Ponting's ERC advanced grant - awarded in 2012) and opened up new research directions.



Accomplished work:

1: Obtained and analysed phylogenetically deep sequence data of selected coding and non-coding genes in selected species. Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes. Chodroff RA, Goodstadt L, Sirey TM, Oliver PL, Davies KE, Green ED, Molnár Z, Ponting CP.

Genome Biol. 2010;11(7):R72.



2: Revealed the expression of coding and non-coding genes in selected species at specific stages of development. The subventricular zone is the developmental milestone of a 6-layered neocortex: comparisons in metatherian and eutherian mammals. Cheung AF, Kondo S, Abdel-Mannan O, Chodroff RA, Sirey TM, Bluy LE, Webber N, DeProto J, Karlen SJ, Krubitzer L, Stolp HB, Saunders NR, Molnár Z.

Cereb Cortex. 2010 May;20(5):1071-81.



3: Generated and analyse knockout mice for non-coding sequences which were selected because of their distinct expression pattern. (We have a manuscript on the anatomical, behavioural and molecular analysis of the first KO mouse ready for submission; Oliver et al.).



4: Examine the effects of selected coding or non-coding sequences to different compartments of the forebrain in vivo and in vitro. Alter the regulatory elements in additional KOs. We have a manuscript almost completed on this area which shall be soon completed and submitted; Sirey et al.).
Exploitation Route Some of our databases: E.g. http://genserv.anat.ox.ac.uk/layers or http://genserv.anat.ox.ac.uk/brainevo. shall be of very general use for the neuroscience and comparative neurobiology community. The knowledge of the coding and non-coding genes during cortical development and adult could be fundamental in understanding normal and abnormal development and disease association. E.g. we provided the first transcriptomic atlas of cerebral cortex in mammals (see: http://genserv.anat.ox.ac.uk/layers from "A transcriptomic atlas of mouse neocortical layers." Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, García-Moreno F, Molnár Z, Margulies EH, Ponting CP. Neuron. 2011 Aug 25;71(4):605-16.

We continued to use transcriptomic analysis in our research after this grant. We collaborated with the Allen Institute of Brain Research and recently published the developmental macaque transcriptomic atlas.
Bakken TE, Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, Szafer A, Dalley RA, Royall JJ, Lemon T, Shapouri S, Aiona K, Arnold J, Bennett JL, Bertagnolli D, Bickley K, Boe A, Brouner K, Butler S, Byrnes E, Caldejon S, Carey A, Cate S, Chapin M, Chen J, Dee N, Desta T, Dolbeare TA, Dotson N, Ebbert A, Fulfs E, Gee G, Gilbert TL, Goldy J, Gourley L, Gregor B, Gu G, Hall J, Haradon Z, Haynor DR, Hejazinia N, Hoerder-Suabedissen A, Howard R, Jochim J, Kinnunen M, Kriedberg A, Kuan CL, Lau C, Lee C-K, Lee F, Luong L, Mastan N, May R, Melchor J, Mosqueda N, Mott E, Ngo K, Nyhus J, Oldre A, Olson E, Parente J, Parker PD, Parry S, Pendergraft J, Potekhina L, Reding M, Riley ZL, Roberts T, Rogers B, Roll K, Rosen D, Sandman D, Sarreal M, Shapovalova N, Shi S, Sjoquist N, Sodt AJ, Townsend R, Velasquez L, Wagley U, Wakeman WB, White C, Bennett C, Wu J, Young R, Youngstrom BL, Wohnoutka P, Gibbs RA, Rogers J, Hohmann JG, Hawrylycz MJ, Hevner RF, Molnár Z, Phillips JW, Dang C, Jones AR, Amaral DG, Bernard A, Lein ES (2016) A comprehensive transcriptional map of primate brain development. Nature, 535(7612):367-375.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://genserv.anat.ox.ac.uk/layers
 
Description I regularly lecture and teach the next generation of medical students (150 contact hours/year). My research has impact on these future clinical doctors.
Sector Education,Healthcare
Impact Types Cultural,Societal

 
Description Senior Founding Member of the University of Oxford Cortex Club
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact The Cortex Club connects researchers at the University of Oxford with world-leading neuroscientists through a unique educational forum dealing with cutting-edge topics and significant challenges in neuroscience. Our events range from small intense debates with up-and-coming scientists to large discussion sessions led by internationally prominent speakers, followed by the opportunity to ask them questions over drinks. News release on the establishment of the cortex club: https://www.dpag.ox.ac.uk/news/cortex-club-celebrates-10-years-of-student-run-talks-and-discussions-for-oxfords-neuroscience-community
URL http://cortexclub.com
 
Description BBSRC Project Grant
Amount £600,000 (GBP)
Funding ID BB/F003285 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2007 
End 04/2010
 
Description Newton Advanced Fellowship (ref: NA140246) to support collaboration with with Dr Xiaoqun Wang, Institute of Biophysics, Chinese Academy of Science, China.
Amount £111,000 (GBP)
Funding ID NA140246 
Organisation Royal Society of Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 03/2018
 
Description Newton International Exchanges (NI140073) with Dr Paul Manger (South Africa) Project title: "The thalamocortical projection in large brained mammals"
Amount £6,000 (GBP)
Funding ID NI140073 
Organisation Royal Society of Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2015 
End 04/2016
 
Description Newton International Exchanges Dr Patricia Garcez (Brazil) (2015/R1, NI150133) Project title: "Transcriptional control of Neuronal migration"
Amount £1,740 (GBP)
Funding ID NI150133 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 08/2015
 
Description The Academy of Medical Sciences Newton Advanced Fellowship
Amount £111,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Department Newton Advanced Fellowship
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 02/2020
 
Title Allen Brain Research Institute - Non Human Primate Developmental Transcriptome Database 
Description The Allen Brain Institute contacted us to advise them on the collection and analysis of the developmental transcriptomic atlas in macaque cerebral cortex. The approach is similar that we developed previously - Hoerder-Suabediessen et al., 2009 - PMID: 23401504 and 2013 - PMID: 23401504; Oeschger et al., 2013 - PMID: 21862448; Belgard et al., 2010 - PMID: 21867878 
Type Of Material Biological samples 
Year Produced 2014 
Provided To Others? Yes  
Impact Our work that was supported by MRC lead to establishing methodologies and approaches that now used by the Allen Brain Institute. We were invited to advise the recent project on Macaque Brain Development Transcriptome where we shall lead the analysis of the subplate layer. This is based on - Hoerder-Suabediessen et al., 2009 - PMID: 23401504 and 2013 - PMID: 23401504; Oeschger et al., 2013 - PMID: 21862448; Belgard et al., 2010 - PMID: 21867878 
URL http://www.alleninstitute.org/science/public_resources/nhp_atlas.html
 
Title High quality RNA from multiple brain regions 
Description We established and optimised a method for the collection of high quality RNA from multiple brain regions, which were simultanelously acquired by laser capture microdissection. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact The publication (PMID:19580671) has been requested from us by numerous groups even before its publication. 
URL http://europepmc.org/abstract/MED/19580671
 
Title Improved protocols for laser capture microdissection 
Description We have developed a simple, flexible, and low-cost method for simultaneously producing RNA from discrete cell groups in embryonic day 15 mouse brain. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact BMC Mol Biol. 2009 Jul 6;10:69. High quality RNA from multiple brain regions simultaneously acquired by laser capture microdissection. Wang WZ, Oeschger FM, Lee S, Molnár Z. 
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=High+quality+RNA+from+multiple+brain+regions+simultaneously...
 
Title Modern tracing methods with carbocyanine dyes. 
Description We optimised conditions for the use of multiple fluorescent carbocuanine dyes in various systems and species (including human postmortem specimen). The advantage of this method is that it can be used on fixed material, therefore it is contributing to 3Rs! 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact We published the summary of our methods: Molnár Z, Blakey D, Bystron I, Carney R, (2006) Tract-tracing in developing systems and in post-mortem human material. Neuroanatomical Tract-Tracing 3: Molecules - Neurons - Systems, Springer/Kluwer/Plenum, NY, (Editors: L Zaborszky, FG Wouterlood, JL Lanciego). Chapter 12:336-393. 
URL http://books.google.co.uk/books?id=-vPcRekAT6oC&pg=PA362&lpg=PA362&dq=L+Zaborszky,+FG+Wouterlood,+JL...
 
Title Murine subplate markers for E15, E18, P8 ages 
Description We performed microarray analysis to identify markers expressed in the murine subplate at various ages. http://europepmc.org/abstract/MED/19008461 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Various neuropathology laboratories have approached us after the publication of: PMID: 19008461 for probes. We are very happy to see that these markers are useful for the wider community (including human neuropathologists). 
URL https://molnar.dpag.ox.ac.uk/subplate/
 
Title Subplate markers for human pathological analysis 
Description We identified several new subtype specific biomarkers for subplate neurons. These can be used in human pathology and in animla models of human pathology (e.g. periventircular leucomalachia). 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact These markers will have impact on neuropathological diagnosis (selective loss of subplate neurons) and perhaps in psychiatry. The markers will enable us to detect subtle neuropathological abnormalities. 
URL http://www.ncbi.nlm.nih.gov/pubmed/21368089
 
Title Subplate neuronal markers - P8 
Description We performed microarray analysis on postbatal 8 days old mouse subplate and layer 6. This data has been published: PMID: 19008461 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Hoerder-Suabedissen A, Wang WZ, Lee S, Davies KE, Goffinet AM, Rakic S, Parnavelas J, Reim K, Nicolic M, Paulsen O, Molnár Z. Cereb Cortex. 2009 Aug;19(8):1738-50. 
URL http://europepmc.org/abstract/MED/19008461
 
Title database on layerspecific cortical transcriptome: http://genserv.anat.ox.ac.uk/layers 
Description This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression levels, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers. 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact http://genserv.anat.ox.ac.uk/layers It is difficult to judge at present, too early, but we noticed that our paper PMID: 21867878 had the highest download in the journal of NEURON after a few weeks of publication. 
URL http://genserv.anat.ox.ac.uk/layers
 
Title A Transcriptomic Atlas of Mouse Neocortical Layers - supplementary website for Belgard, et al. (2011) 
Description A transcriptomic atlas of mouse neocortical layers. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, García-Moreno F, Molnár Z, Margulies EH, Ponting CP. Neuron. 2011 Aug 25;71(4):605-16. We sequenced transcriptomes from layers 1-6b of different areas (primary and secondary) of the adult (postnatal day 56) mouse somatosensory cortex to understand the transcriptional levels and functional repertoires of coding and noncoding loci for cells constituting these layers. A total of 5,835 protein-coding genes and 66 noncoding RNA loci are differentially expressed ("patterned") across the layers, on the basis of a machine-learning model (naive Bayes) approach. Layers 2-6b are each associated with specific functional and disease annotations that provide insights into their biological roles. This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression levels, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers. 
Type Of Material Database/Collection of data 
Year Produced 2011 
Provided To Others? Yes  
Impact This is the first website that describe the layer-specific transcriptome of the adult mouse cortex using deep sequencing method. This enables the study of splice variants and non-coding transcripts. 
URL http://genserv.anat.ox.ac.uk/layers
 
Title Online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. 
Description Here we present gene expression evidence for distinct roles of the mouse subplate across development as well as unique molecular markers to extend the repertoire of subplate labels. Performing systematic comparisons between different ages (embryonic days 15 and 18, postnatal day 8, and adult), we reveal the dynamic and constant features of the markers labeling subplate cells during embryonic and early postnatal development and in the adult. This can be visualized using the online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. We also identify embryonic similarities in gene expression between the ventricular zones, intermediate zone, and subplate, and distinct postnatal similarities between subplate, layer 5, and layers 2/3. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Our database (https://molnar.dpag.ox.ac.uk/subplate/) help the general research community to find suitable markers to reveal subplate, the early generated, largely transient cell population. 
URL https://molnar.dpag.ox.ac.uk/subplate/
 
Title Web resource for adult forebrain expression in mouse and chicken at http://genserv.anat.ox.ac.uk/brainevo. 
Description We explored which genes are actively transcribed in the regions of controversial ancestry in a representative bird (chicken) and mammal (mouse) at adult stages. We conducted four analyses comparing the expression patterns of their 5,130 most highly expressed one-to-one orthologous genes that considered global patterns of expression specificity, strong gene markers, and coexpression networks. we provide a Web resource for adult forebrain expression in mouse and chicken at http://genserv.anat.ox.ac.uk/brainevo. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact This dataset not only will enable insights into telencephalic gene expression evolution, but also can facilitate future functional investigations. For example, the cross-species marker lists for striatum and hippocampus can readily be expanded using the advanced search feature on the website. 
URL http://genserv.anat.ox.ac.uk/brainevo
 
Description Comprehensive spatiotemporal map of the primate brain transcriptome - adviser to Allen Brain Research Institute 
Organisation Allen Institute for Brain Science
Country United States 
Sector Academic/University 
PI Contribution My laboratory has been involved in the planning and the analysis of this large transcriptomic analysis of the developing macaque brain. In particular we advised on the laser dissection of embryonic cortical layers and on the analysis and interpretation of the data. The paper is under review in Nature, I pasted the abstract below: The detailed transcriptional underpinnings of brain development and neuropsychiatric disease are poorly understood, particularly in humans and closely related primate model organisms. To fill this gap, we describe a comprehensive spatiotemporal transcriptional atlas of rhesus monkey brain development that combines dense pre- and postnatal temporal coverage with fine anatomical parcellation of cortical and subcortical regions associated with human neurological and psychiatric disease. Using these data, we show high rates of expression change throughout prenatal and early postnatal development that taper off sharply during childhood, which are of comparable magnitude in both dividing precursors and maturing postmitotic neurons. Prenatal patterning varies dramatically from postnatal stages, while acquisition of adult-like molecular profiles for cortical layers and areas occurs gradually but surprisingly late in postnatal life. Different cell populations show discrete but overlapping expression profiles and show evidence for differences in developmental timing but also an unexpected degree of synchrony of specific developmental processes. Comparing rhesus gene expression trajectories to human, rat and mouse reveals large-scale differences between primates and rodents and a number of genes with human-specific temporal patterning. This transcriptional map, along with corresponding neuroimaging reference and cellular resolution gene expression data, provide a rich, freely accessible resource for understanding spatiotemporal transcriptional dynamics of primate and human brain development.
Collaborator Contribution All experiments and tissue processing was done by the Allen Brain Research Institute.
Impact The output will be published on the appropriate website for the DEVELOPING non-human primate developing atlas, similarly to the adult website: http://www.blueprintnhpatlas.org/
Start Year 2014
 
Description I helped with the new edition of the brain part of the Kaufman's Atlas of Mouse Development. 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Brain Development Z Molnár, DJ Price Kaufman's Atlas of Mouse Development Supplement: With Coronal Sections, 239
Collaborator Contribution Brain Development Authors Zoltán Molnár, David J Price Publication date 2015/9/23 Journal Kaufman's Atlas of Mouse Development Supplement: With Coronal Sections Pages 239 Publisher Academic Press Description This chapter is divided into several sections that follow the chronological development of the mammalian brain (Goffinet and Rakic, 2000). It starts with a discussion of the specification of future neural tissue and the early types of signaling that contribute to the regionalization of the central nervous system (CNS)(E5-E12). Then, focusing mainly on the cerebral cortex, the text describes in detail how different cell types are generated and sets out some general principles underlying the layered structure of the mature neocortex (E12-P8). The mature ... Scholar articles Brain Development Z Molnár, DJ Price - Kaufman's Atlas of Mouse Development Supplement: , 2015 Related articles
Impact https://books.google.co.uk/books?hl=en&lr=&id=U-GcBAAAQBAJ&oi=fnd&pg=PA239&ots=rC3BP_nnya&sig=dq96eq2DhH-R89_Zbo2O29gICGM#v=onepage&q&f=false
Start Year 2015
 
Description Subplate Gene Expression Atlas 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution The Subplate Gene Expression Atlas illustrates the cortical expression patterns of 426 selected genes. These genes were identified by both microarray/RNA seq and in situ hybridization studies as preferentially expressed in subplate at at least one developmental age (E15, E18, P4/P7/P8 and Adult). The expression patterns illustrated in the Atlas are derived from published or publicly available in situ hybridization images. Expression levels were categorized for the illustration according to two criteria: abundance of cells (abundant vs sparse) and expression level (no labeling detected vs weak labeling vs strong labeling).
Collaborator Contribution A microarray based approach was used to identify genes expressed at a higher level in the mouse subplate compared to overlying cortical plate at embryonic ages E15.5 and E18.5 and subplate compared to overlying layer 6a at postnatal P8 (Affymetrix Gene ST1.0 at E15, Affymetrix 430 2.0 for E18.5 and P8). Data was RMA normalized and putatively differential gene expression (>1.5-fold higher in subplate, nominal p<0.05) determined. High-throughput sequencing data was used to identify genes expressed at a higher level (>1.5 fold) in the adult mouse subplate/layer 6b compared to the adjacent layer 6a. In total, 1642 genes were identified as potentially SP enriched at least at one age. Of these, 426 genes could be confirmed as SP enriched using published or publicly available databases including Allen Mouse Brain Atlas (Adult), Allen Developing Mouse Brain Atlas (E15.5, E18.5, P4 and P14), Genepaint.org (E14.5, P7 and Adult) and or our own in situ hybridization or immunohistochemistry experiments. The schematic results of this are presented here in the "Subplate Gene Expression Atlas". Genes with uniform or no labelling, or for which no images could be found, were not included. Using the above approach, we selected against genes that are subplate expressed, but are additionally expressed in layer 6a at equal or higher levels. Furthermore, there may be subplate specific or enriched genes not identified by the microarrays. Thus, genes important for the differentiation of the deep cortical layers or those relevant in the specification of subplate prior to E15.5 may not be included here. This Subplate Gene Expression Atlas is an ongoing project and over time more genes identified by other sources may be added if there is convincing evidence of their subplate enriched expression at the above time points.
Impact Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia. Hoerder-Suabedissen A, Oeschger FM, Krishnan ML, Belgard TG, Wang WZ, Lee S, Webber C, Petretto E, Edwards AD, Molnár Z. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3555-60.
Start Year 2012
 
Description Subplate transcriptome analysis in macaque and human 
Organisation Allen Institute for Brain Science
Country United States 
Sector Academic/University 
PI Contribution We are currently analysing data (that is very similar to our original description of the subplate-specific transcriptome in mice - see Hoerder-Suabedissen et al., 2009; Oeschger et al., 2013) in macaque in collaboration with the Allen Brain Institute, Seattle, USA.
Collaborator Contribution We defined layers on cytoarchitectonic distinctions, advised ABI on the location and numbers of dissected areas. Provided our data for the mouse - macaque comparisons.
Impact http://www.blueprintnhpatlas.org/
Start Year 2012
 
Description Brain Diaries Exhibition - Museum of Natural History, University of Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Extract from the introduction from the exhibition website: Baby, child, teenager, adult
Throughout your life, your brain undergoes extraordinary changes.
Fascinating physical developments in your brain unlock each new chapter as you grow. And with billions of neurons and trillions of connections, it responds to your experiences to make you the person you are.
What does the latest research tell us about how
our brains work, from the minute we are conceived to the moment we die?
Explore the
Year(s) Of Engagement Activity 2016
URL http://www.oum.ox.ac.uk/braindiaries/
 
Description C'est quoi la neurocience? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I gave a presentation (in French) to 10-12 years old students at the International "European" School at Culham. The presentation took 2 hours and received very enthusiastic response form pupils, teachers and subsequently from parents.

The school asked me to do this presentation again every year.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014
 
Description Interview to the OX Magazine on Brain Awareness Week 2017 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact From the 10th March the Museum of Natural History are opening an exhibition and series of events on the mysteries of neurological development - Brain Diaries. I was approached by the OX Magazine to give an interview and discuss the highlights of this exhibition and also my own research. This was produced for the general public in Oxfordshire.
The interview can be accessed on: http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
Year(s) Of Engagement Activity 2016
URL http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
 
Description Molnar Laboratory FaceBook Page with over 200 followers 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Molnar Laboratory has its own Facebook page: https://www.facebook.com/molnarlab/
There are over 200 followers. The FB page advertises seminars, lectures, conferences and keeps in touch with alumni of the laboratory.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019
URL https://www.facebook.com/molnarlab/
 
Description Molnar Laboratory has its own FaceBook page 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Molnar Laboratory has its own Facebook page: https://www.facebook.com/molnarlab/
There are over 200 followers. The FB page advertises seminars, lectures, conferences and keeps in touch with alumni of the laboratory.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019,2020
URL https://www.facebook.com/molnarlab/
 
Description New Theories on the Origin of Cerebral Cortical Convolutions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New Theories on the Origin of Cerebral Cortical Convolutions


http://www.neuroscience.ox.ac.uk/about/news/new-theories-on-the-origin-of-cerebral-cortical-convolutions/

no actual impacts realised to date
Year(s) Of Engagement Activity 2012,2013,2014
URL http://www.hfsp.org/frontier-science/awardees-articles/new-theories-origin-cerebral-cortical-convolu...
 
Description Oxford - McGill Mini Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact https://www.mcgill.ca/brain/international-partners/oxford-university/oxford-neuroscience-news

On 14th January 2014 a mini Symposium organised by Andrew King and Zoltán Molnár served as the first joint cluster meeting between the systems and cellular neuroscience groups of the DPAG. The meeting covered a wide range of topics focussed around "Mammalian cerebral cortical circuits".

The joint cluster meeting brought together groups who are experts in the field of cerebral cortical circuit formation and plasticity in mammals. Their expertise extends from neurogenesis and neuronal migration to the establishment and plasticity of connections. These groups use various techniques: laser-scanning photo stimulation, 2-photon microscopy, confocal microscopy, electrophysiology and behavioural testing. Their aim is to understand how mammalian cortical neurons control cortical development and plasticity and how they are integrated into functional cortical circuitry responsible for some of the most sophisticated sensory and motor processing.

The cluster meeting was linked to the visit of Professor Anne Mc Kinney, Vice Chair of McGill's Brain Institute, who delivered a keynote lecture on "Dendritic spines, autism and epilepsy". Her laboratory has made a great contribution to the insights into synapse maintenance and plasticity in the mammalian cerebral cortex and hippocampus.

The symposium gave an excellent opportunity to continue to build links between McGill and Oxford Neuroscience.
Year(s) Of Engagement Activity 2013,2014
URL https://www.mcgill.ca/brain/international-partners/oxford-university/oxford-neuroscience-news
 
Description Professor Molnar has a Twitter Account with Science Focus 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Molnar has a Twitter Account (https://twitter.com/ZoltanMolnar64) that has outreach function. Seminars, lectures and conferences are advertised. It also draws attention to recent publications and presentations. There are over 300 followers.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019,2020
URL https://twitter.com/ZoltanMolnar64
 
Description Professor Zoltán Molnár features in BBC programme 'How the NHS Changed our World' 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact https://www.dpag.ox.ac.uk/news/professor-zoltan-molnar-features-in-bbc-programme-how-the-nhs-changed-our-world

The BBC recently visited Zoltán Molnár, Professor of Neuroscience here in DPAG, to discuss the research undertaken by Sir Charles Scott Sherrington, during his time in the Laboratory of Physiology, as part of a new series on 'How the NHS Changed our World'.

Sherrintgon kept hundreds of of microscope slides in a specially constructed Histological Box, which has been preserved and is now kept by Zoltán here in the Department.

In the interview, Zoltán sheds light on how Sherrington and his colleagues would shed their skin for the sake of scientific research. Sherrington's notes reveal how popular self-experimentation was in those days.

The interview can be viewed here and you can also watch the whole episode on iPlayer.
Year(s) Of Engagement Activity 2018
URL https://www.dpag.ox.ac.uk/news/professor-zoltan-molnar-features-in-bbc-programme-how-the-nhs-changed...