Role of Neurotrophins in the Development of the Mammalian Nervous System

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

An important area of research of my laboratory is focused on the in vivo dissection of the function of the domains of Trk receptor complex structure in both the extracellular and intracellular regions to identify mechanisms and/or proteins that regulate receptor activation and function in specific cell types and neuronal circuitries. So far, we have shown that a three amino-acid intracellular domain in the juxtamembrane region of TrkA (KFG) regulates the receptor ubiquitination and function. With this mouse model we identified a new function of TrkA signaling in the basal forebrain cholinergic region in the regulation of fear response and fear expression. Our findings also have profound implications for patients undergoing cancer therapy. The finding that TrkA expressing Basal Forebrain Cholinergic neurons regulate fear circuitries and may influence development of PTSD raises the question of whether treatment of cancer patients with pan-Trk inhibitors put them at higher risk of developing PTSD. Currently, we have begun the characterization of the in vivo function of the leucine rich repeat (LRR) domain in the extracellular region of the TrkB receptors in a recently generated mouse model with such mutation. Since LRRs are found in many neural cell-adhesion molecules and are implicated in axon guidance, target selection, synapse formation and in synaptogenic adhesions we expect that this work will help us identify the molecular mechanism underlying TrkB function in the regulation of complex behaviors. In summary, the overreaching goal of our research is to dissect the multitude of functions of neurotrophins by using the mouse as a genetically amenable in vivo system to inform pharmacological interventions to modulate the activity of neurotrophins and their receptors in disease.