OVEREXPRESSION OF NGF WITHIN THE HEART OF TRANSGENIC MICE CAUSES HYPERINNERVATION, CARDIAC ENLARGEMENT, AND HYPERPLASIA OF ECTOPIC CELLS

Nerve growth factor (NGF) supports the survival of developing sympathe tic and a subpopulation of sensory neurons. In the adult it participat es in maintenance of the neurotransmitter phenotype of responsive neur ons. The amount of NGF synthesized by a given target tissue determines its final innervation density; those developing neurons that fail to receive sufficient NGF undergo apoptosis. In order to examine the rami fications of this principle in the context of a specific target organ, a transgenic mouse model was developed in which NGF expression was in creased in developing and adult cardiac tissue by placing a NGF minige ne under the transcriptional control of the cardiac-specific cr-myosin heavy chain promoter. Transgenic mice developed cardiac enlargement s econdary to both an increase in myocardial mass and the presence of an abundant ectopic cell population. Immunohistochemical analyses with t he neural marker S-100 revealed staining of a subpopulation of ectopic cells, suggesting their derivation from the neural crest. Whereas imm unostaining for the neuronal-specific protein neuron-specific enolase demonstrated labeling of another subpopulation of ectopic cells within the heart. Measurements of cardiac tissue catecholamine levels reveal ed a marked elevation in transgenic mice, consistent with sympathetic hyperinnervation. Analysis of mediastinal sympathetic ganglia revealed increases in both the size and the number of neurons. In this model, increased expression of NGF produced hyperinnervation of the heart, pa thological cardiac growth, and the recruitment and/or expansion of an ectopic, neural crest-derived cell type. (C) 1995 Academic Press, Inc.