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Human neurogenesis is a vibrant field of research with deep therapeutic potential.
The postnatal rodent subventricular zone generates tens of thousands of neurons every day.
We study postnatal and adult mammalian brain stem cells to uncover fundamental developmental mechanisms and disease pathogenesis.
The Szele group is working on translational as well as fundamental developmental neurobiological questions in health and disease.
Our main discovery platform are the two stem cell niches of the brain - the subventricular zone (SVZ) and the dentate gyrus (DG). The SVZ and DG neurogenic niches contain stem cells, transit amplifying progenitors and neuroblasts. They are convenient biological systems to study fundamental developmental questions since one can easily modulate gene expression in them. We investigate the role of the SVZ in models of neurodegeneration and neuropsychiatric disorders. We also study human neurogenesis in postmortem sections and with induced pluripotential stem cells. We are interdisciplinary and have many excellent collaborators.
The neurogenic niches harbour stem cells that attempt to repair brain injury but do so inefficiently. Thus, many of our studies seek to understand how the SVZ and DG respond to disease with the ultimate goal of using molecular insights to augment neurogenesis and enhance progenitor migration towards brain injury. We were the first to show increased neurogenesis after injury and are now partnering with Jan Czernuszka to develop engineered scaffolds for stem cell transplantations. We have focused on Galectin-3 (Gal-3) a pro-inflammatory protein we showed is necessary for SVZ neuroblast migration. We also found Gal-3 is necessary for angiogenesis after stroke and that it is upregulated in multiple sclerosis (MS). With Hiroko Isoda we are testing the neurogenic properties of phytochemicals and nutraceuticals. Together with Angela Russell and Steve Davies we have started OxStem Neuro an innovative new company screening small molecules for their potential to stimulate endogenous stem cells and increase adult neurogenesis.
The Szele group are actively pursuing novel mechanistic insight into epigenetic and lncRNA regulation of neurogenesis. Using floxed Eed and Ezh2 mice, we found that different components of the Polycomb repressive complex 2 regulate distinct neurogenic events. We showed with Keith Vance that lncRNA Paupar is necessary for SVZ/OB neurogenesis. Several of the genes we study such as Gal-3 and lncRNAs impact tumorigenesis and gliomas can arise from SVZ cancer stem cells. Together with Ian Tomlinson we knocked the human IDH1R132H mutation into the SVZ causing a gliomagenic phenotype. We are also working with Eric O'Neill on tumorigenic signalling pathways in the SVZ.
We also have a longstanding interest in the role of abnormal neurodevelopment in neuropsychiatric disorders. We use an integrated suite of animal models, human post-mortem sections and human induced pluripotential stem cells (iPSC) to study Autism and Schizophrenia. In particular we are studying how mutations in the dysbindin gene functionally interact with inflammation to regulate neurogenesis in a murine gene x environment interaction model. Istvan Adorjan, a former postdoc in the lab and now running an independent group at the Semmelweis University (Budapest), demonstrated that the striatum contains fewer calretinin+ interneuron in patients with autism. We are now working with Dr. Adorjan on studies of postmortem human sections in other neuropsychiatric disorders. In collaboration with Tony James and Sally Cowley we are growing iPSC and olfactory stem cells from subjects with adolescent onset schizophrenia
The Szele lab uses a wide range of in vivo and in vitro techniques including stem cell cultures, migration assays, in vivo electroporation, over expression and knockdown, Cre-lox conditional knockouts, etc. We have used 2-photon time-lapse microscopy in slices to record and quantitatively analyse cell behaviours in the SVZ and are developing in vivo approaches of imaging neurogenesis.
We have weekly lab meetings Tuesdays from 9-10.30 AM. Please email Francis Szele if you would like to join us for one or more of these.
We welcome enquiries for collaboration, postdoctoral fellowships or studentships.
14 March, 2018
08 FEbruary, 2018
Congratulations to Farah Allamari for her paper accepted in the EMBO J. Farah is co-first author of: Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Olfactory Bulb Neurogenesis. This work was spearheaded by our collaborator Keith Vance at the University of Bath.
ABSTRACT Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and mechanisms of action remain poorly understood. Paupar, a CNS expressed lncRNA, controls neuroblastoma cell proliferation by binding and modulating the activity of genome-wide transcriptional regulatory elements. We show here that Paupar transcript directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. Paupar promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through formation of a ribonucleoprotein complex containing Paupar, KAP1 and the PAX6 transcription factor. Paupar-KAP1 genome-wide co-occupancy reveals a 4-fold enrichment of overlap between Paupar and KAP1 bound sequences, the majority of which also appear to associate with PAX6. Furthermore, both Paupar and Kap1 loss of function in vivo disrupts olfactory bulb neurogenesis. These observations provide important conceptual insights into the trans-acting modes of lncRNA-mediated epigenetic regulation, the mechanisms of KAP1 genomic recruitment and identify Paupar and Kap1 as regulators of neurogenesis in vivo.
01 FEBRUARY, 2018
Good luck to Bin Sun in his new Postdoctoral Fellowship. Bin has joined Jesus Gil's lab at Imperial in London to study senescence. We wish him all the best and thank him for his excellent contributions to the lab. We'll miss you Bin!
07 January, 2018
Luana Campos Soares successfully passed her transfer of status to DPhil viva. Well done Luana! Luana is a graduate student in Oncology working on a collaboration with Prof. Eric O'Neill and is determining mechanistic interactions of Gal-3 and Hippo signalling in inflammation and cancer in the SVZ.
24 October, 2017
Congratulations to fiishing DPhil student Martin Ducker who has pitched his cell assay to block infiltration of highly aggressive glioblastoma brain tumour and triumphed in first place with unanimous praise from the panel of expert judges in the "IMAGINE IF! Oxford Accelerator competition.
07 October, 2017
Congratulations to Bin Sun whose paper is accepted by Cerebral Cortex. "Polycomb protein Eed is required for neurogenesis and cortical injury activation in the subventricular zone"
28 August, 2017
We welcome our new Postdoc Dr. Noelia Geribaldi Doldan. Noelia joins us from University of Cadiz and will lead our collaboration with Prof. Hiroko Isoda at University of Tsukuba.
28 August, 2017
Scientific Reports publishes 3D cell printing paper - collaboration with Bayley group, "High-Resolution Patterned Cellular Constructs by Droplet-Based 3D Printing"
27 June, 2017
Brain publishes Istvan Adorjan's paper, "Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder"
1 April, 2017
We welcome 4 new rotation students! Abishek Arora, Master's in Neuroscience rotation student (April - August 2017), Victor Lu, Master's in Neuroscience rotation student (April - August 2017), Ben Cheung, undergraduate medical student from Chinese University of Hong Kong (April/May 2017), Thomson Loong, , undergraduate medical student from Chinese University of Hong Kong (April/May 2017)