Contrasting effects of overexpressing the neurotrophin receptors TrkA and TrkB during development

Neurotrophins and their cognate receptors are part of an important signalling system in the vertebrate nervous system. This includes the control of cell survival during the development of the peripheral nervous system. Whilst the neurotrophins and their respective tyrosine kinase receptors are closely related in structure, unexpected differences have begun to appear with regard to their function. In particular, the tropomyosin receptor kinase A (TrkA) has been reported to cause the death of neurons in the absence of its neurotrophin ligand, nerve growth factor (NGF). By contrast, there have been no indications as of yet that the expression of the closely related brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) receptor TrkB induces the death of neurons during development. A better understanding of the function of these receptors has important implications as unlike TrkA in the peripheral nervous system, TrkB is widely expressed in the central nervous system where BDNF does not seem to play a significant role as a survival factor. To further explore the role of these receptors, novel in vitro and in vivo models were generated that allowed the conditional overexpression of TrkA and TrkB. It was found that the ubiquitous overexpression of TrkA from the earliest stages of mouse gestation led to a perinatal death phenotype, whilst mice overexpressing TrkB were viable and fertile. Detailed histological examination indicated that the overexpression of TrkA led to the loss of neurons known to depend on NGF for their survival during development. Indeed TrkA-overexpressing mice phenocopy mutants lacking both Ngf alleles. By contrast, the postnatal survival of TrkB-overexpressing mice was unimpaired, despite a loss of cranial sensory neurons approaching what has been reported for mice lacking the genes encoding BDNF and NT4. Potential explanations for these surprising observations are discussed.