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Growth Factor Signaling

Our lab investigates the role of growth factors in the nervous system under pathological conditions. Neurotrophic molecules are in the focus of several research groups as possible treatments for neurological or psychiatric disorders. Unfortunately, nearly all therapeutic trials in  patients were unsuccessful so far. It appears that growth factor receptors cannot be sufficiently activated in the aging brain to exert significant protective or restorative effects. Therefore, the aim of our work is to identify signaling pathway components downstream of growth factor receptors 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 of the brain. Over the years, novel insights into FGF receptor (FGFR) signaling in health and disease were obtained through targeted and inducible mouse knock-out models, optogenetics and advanced imaging techniques. Stimulation of FGF receptors remains a key to promote neurogenesis, neuronal protection, axonal regeneration and re-myelination in the injured nervous system. Our research focuses on signaling and transport of FGFR1 (Csanaky et al. 2019).

Among the negative feedback inhibitors of FGFR1 induced signaling are the Sprouty proteins. Down-regulation or knock-out of Sprouties promotes 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 mice exhibit elevated MAP kinase (ERK) activity and enhanced axon outgrowth in response to nerve injury. Following sciatic nerve crush significantly more myelinated axons regenerate in Sprouty2+/- mice which is accompanied by faster recovery of function and increased expression of GAP-43 (Marvaldi et al. 2015).

Recently, we investigated a combined approach to promote long-distance axon growth: Dual-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, injection of siRNAs against Sprouties into rat brains reduces the lesion size in response to endothelin-induced vasoconstriction (a model for stroke, Klimaschewski et al. 2016). Secondary brain damage is also significantly diminished in Sprouty2/4 heterozygous knockouts following kainate-induced epileptogenesis,. These mice exhibit less neuronal loss than their wildtype littermates in the hippocampus which is accompanied by increased reactive astroglial proliferation (Thongrong et al. 2016).

Furthermore, Sprouty2 is a key regulator of tumor formation in the brain (Park et al. 2018). Sprouty2 is up-regulated in malignant gliomas and correlates with reduced survival in patients. Knockdown of Sprouty2 significantly impairs proliferation of glioblastoma. 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