Neurotrophin-regulated signalling pathways

Abstract

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low‐avoidance) and resistance (Roman high‐avoidance) to stress‐induced depression

“…Upon its synthesis in the neuronal cell body, BDNF is anterogradely transported to the axon terminal and released in the synaptic cleft (Altar & DiStefano, 1998; Conner, Lauterborn, Yan, Gall, & Varon, 1997; Farhadi et al., 2000). The effects of BDNF are mediated by the activation of intracellular signaling pathways upon high affinity binding to the trkB receptor, a member of the trk family of tyrosine kinase receptors (Binder & Scharfman, 2004; Reichardt, 2006). …”

Expression of NGF, BDNF and their receptors in subcutaneous adipose tissue of lactating cows

“…Neurotrophin/Trk signaling is regulated by a variety of intracellular signaling cascades, transmitting positive signals to promote survival and growth. On the other hand, p75NTR transmits both positive and negative signals (Reichardt, 2006). To date, neurotrophins have been mainly studied in nervous cells, but, as multifunctional growth factors, they can exert various effects through their receptors on non-neuronal cells such as testis (Müller et al, 2006), thymus (Maroder et al, 2000), skin (Di Marco et al, 1993), salivary glands and mammary ducts (Shibayama and Koizumi, 1996;Sariola, 2001) and ovine mammary glands (Colitti, 2015).…”

Expressions of Axl and Tyro-3 receptors are under regulation of nerve growth factor and are involved in differentiation of PC12 cells

“…As we know, the regulatory effects of NGF on neuronal differentiation and development are exerted through the binding of NGF to its high affinity receptor TrkA, which is also a member of receptor tyrosine kinases family [12] . It is well known that NGF triggers PC12 differentiation through the TrkA receptor.…”