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We study postnatal and adult mammalian brain stem cells to uncover fundamental developmental mechanisms and disease pathogenesis.

Szele group
Newborn neurons in the olfactory bulb. Stem cells and progenitors were electroporated in the subventricular zone lining the lateral ventricle to introduce plasmid DNA encoding for a fluorescent protein that labels the membranes (purple) and another that labels nuclei (green). Seven days later they had migrated to the Olfactory Bulbs and started to differentiate into mature neurons. (Szele lab, unpublished)

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 quite a bit on Galectin-3 (Gal-3) a proinflammatory protein we found is necessary for SVZ neuroblast migration. We showed that Gal-3 is also necessary for angiogenesis after stroke and that it is upregulated in multiple sclerosis (MS). We have recently discovered that Gal-3 regulates Wnt and BMP signalling, thereby controlling postnatal SVZ gliogenesis. 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 find that different components of the Polycomb repressive complex 2 regulate distinct neurogenic events. We have shown that the lncRNA Visc-2 is dispensable for SVZ neurogenesis but we are now collaborating with Keith Vance and Xiaohua Shen on two other lncRNAs that have fascinating functions in the SVZ. 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 have shown with Xin Lu that ASSP2 regulates inflammation in the SVZ and are working with Eric O'Neill on tumorigenic signalling pathways. 

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, in collaboration with David Greaves. We also demonstrated that the striatum contains fewer interneuron subtypes in patients with autism. 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.

07 October, 2017

 

 

 

Szele lab members

Selected publications

Related research themes