Our major fields of interest are axotomy-induced neuronal plasticity and fibroblast growth factor (FGF) receptor signaling in the nervous system.
Extracellular signals activate receptor-triggered intracellular signal transduction pathways. At the same time, receptor tyrosine kinases initiate a cascade of events of ‘negative signaling’ thereby decreasing the amplitude of positive signals and modulating the level of growth factor-induced stimulation. Hence, the same receptor simultaneously induces positive and negative signals.
Receptor tyrosine kinases are activated by ligand binding, autophosphorylated and ubiquitinated, i.e., the small molecule ubiquitin is attachted to lysine residues at various sites. Following internalization the receptor is either recycled or degraded in the endosomal/lysosomal pathway. Negative receptor signaling involves the coordinated action of ubiquitin ligases like c-Cbl, adaptor proteins like Grb2, negative feedback molecules like Sprouty, cytoplasmatic kinases and phosphoinositol metabolites.
We are particularly interested in the signaling and trafficking of fibroblast growth factor receptor type 1. FGFR1 and regulators of FGFR1 signaling, such as Sprouty proteins, are abundant in the nervous system and important for brain development and disease.
Neurotrophic factors and their receptors have been in the focus for the development of therapeutic treatments for neurological and psychiatric disorders over many years. Unfortunately, growth factor therapies have been largely unsuccessfull in the past. It became clear that receptor tyrosine kinases and their signaling pathways may not be sufficiently activated in the aging brain to exert significant neuroprotective, neurorestorative and stimulatory effects on diseased neurons (possibly due to receptor down-regulation or truncation). Therefore, the aim of our laboratory is to identify intracellular signaling molecules downstream of growth factor receptors which may act as pharmacological targets to increase pro-survival and pro-regenerative mechanisms in the diseased peripheral and central nervous system.
Sprouty proteins form a small family of negative feedback inhibitors of growth factor induced intracellular signaling, in particular, the RAS/RAF/MEK/ERK pathway. In the nervous system, 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.
We have shown that primary sensory neurons dissociated from Sprouty2 knock-out ganglia exhibit elevated ERK activity and enhanced axon outgrowth. 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).
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, 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). Currently, we are investigating the role of Sprouty2 in astrocyte and glioma signaling and proliferation in more detail.