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Several hundred new neurons are born in the the adult human hippocampus on a daily basis.
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 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 showed is necessary for SVZ neuroblast migration. We showed that Gal-3 is necessary for angiogenesis in stroke and that it is upregulated in multiple sclerosis (MS). We are now showing that Gal-3 regulates Wnt and BMP signalling, thereby controlling postnatal SVZ gliogenesis. 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 are showing 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 the 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 are also demonstrating that potions of the human forebrain contain 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.
19 April, 2017
19 April, 2017
Brain accepts Istvan Adorjan's paper,
"Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder"
Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- gender matched patients with autism spectrum disorder and controls ranging in age from 13 to 69 years. Autism subjects had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.
Istvan recently finished a three year postdoc in the lab funded by the Simons and Dana foundations. He has now returned to his faculty position at the Semmelweis University in Budapest, Hungary.
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)
List of funding bodies
MRC, OxStem, Qatar Foundation
SVZ Neuroblasts immunostained for Dcx, beta III-tubulin and PSA-NCAM