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Growth Factor Signalling

Our lab investigates the role of growth factors in the nervous system under pathological conditions. Neurotrophic factors in particular are in the focus of several labs as possible treatments for neuropsychiatric disorders. Unfortunately, nearly all therapeutic trials were unsuccessful so far. It became clear that growth factor receptors cannot be sufficiently activated in the aging brain to exert significant protective or restorative effects (possibly due to receptor down-regulation). The aim of our work is to identify signalling pathway components downstream of receptor tyrosine kinases which may act as pharmacological targets to increase pro-survival and pro-regenerative mechanisms in the diseased nervous system.

Fibroblast growth factors (FGFs) are important for the development and repair not only of the skin but also of the brain. Over the years novel insights into FGF receptor (FGFR) signalling in health and disease were obtained through targeted and inducible mouse knock-out models, optogenetics and super-resolution imaging. With regard to the nervous system, stimulation of FGF receptors remains a key to promote neurogenesis, neuronal protection, axonal regeneration and myelination. Our research focuses on signalling and transport of FGFR1 (Csanaky et al. 2019).

Among the negative feedback inhibitors of FGFR1 induced signalling are the Sprouty proteins. Down-regulation or knock-out of Sprouties promote recovery from mechanical, vascular or excitotoxic brain lesions. Applying three different in vivo lesion models we demonstrated that reduction of Sprouties in neurons and glial cells improves neuronal survival and axonal regeneration in the central and peripheral nervous system. For example, we have shown that primary sensory neurons dissociated from Sprouty2 knock-out ganglia exhibit elevated MAP kinase (ERK) activity and enhanced axon outgrowth in response to injury. Following sciatic nerve crush, significantly more myelinated axons regenerate in Sprouty2+/- mice which is accompanied by faster recovery of sensomotor performance, higher number of motor endplates in distal muscles and increased expression of GAP-43 (Marvaldi et al. 2015).

In our recent study we investigated a combined approach to promote long-distance axon growth: Interference with Sprouty2 and PTEN, an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway. The results clearly show that their simultaneous knockdown in cultured neurons promotes axon elongation stronger than the knockdown of each molecule alone (Jamsuwan et al. 2020).

With regard to the CNS, injections of siRNAs against Sprouties into rat brains reduce the lesion size in response to endothelin-induced vasoconstriction (a model for stroke, see Klimaschewski et al. 2015). In another CNS lesion model, kainate-induced epileptogenesis, secondary brain damage is significantly diminished in Sprouty2/4 heterozygous knockouts. These mice exhibit less neuronal loss than their wildtype littermates after kainate injection into the hippocampus which is accompanied by reduced neuronal migration (dispersion of granule cells) and increased astroglial proliferation (Thongrong et al. 2016).

Sprouty2 is also a key regulator of glioma formation in the brain (Park et al. 2018). It is up-regulated in malignant gliomas and correlates with reduced survival in patients. Knockdown of Sprouty2 significantly impairs proliferation of glial tumors. Silencing of Sprouty2 increases EGF-induced ERK and AKT activation concomitant with premature S-phase entry of glioblastoma cells. Consistent with these findings, DNA damage response and cytotoxicity are increased. Therefore, interference with Sprouties may provide a novel therapeutic strategy to increase and prolong ERK activation under various pathological conditions.

For more details on the role of Sprouties in the nervous system please have a look at our recent review (Hausott and Klimaschewski 2018).

Funding

Austrian Science Fund (FWF), Tyrol Science Fund and MUI-START

Institute of Neuroanatomy

 

Institute of Neuroanatomy
Prof. Dr. med. Lars Klimaschewski

 
Innsbruck Medical University
Department of Anatomy, Histology & Embryology
Institute of Neuroanatomy
Muellerstrasse 59
6020 Innsbruck, Austria
 
TEL +43 512 9003 71160
FAX +43 512 9003 73170
Email: lars.klimaschewski@i-med.ac.at

 

Institute of Neuroanatomy
Prof. Dr. med. Lars Klimaschewski

 
Innsbruck Medical University
Department of Anatomy, Histology & Embryology
Institute of Neuroanatomy
Muellerstrasse 59
6020 Innsbruck, Austria
 
TEL +43 512 9003 71160
FAX +43 512 9003 73170
Email: lars.klimaschewski@i-med.ac.at