Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis

Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis

^*Neural Development Group and ^†Molecular Embryology Section, ABL-Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, MD 21702; ^¶Department of Pathology, Children’s Hospital, Boston, MA 02115; and ^‖Department of Medicine, Cornell University Medical College, New York, NY 10021

Communicated by Rodolfo R. Llinas, New York University Medical Center, New York, NY (received for review May 19, 1997)

Abstract

We have generated null mutant mice that lack expression of all isoforms encoded by the trkC locus. These mice display a behavioral phenotype characterized by a loss of proprioceptive neurons. Neuronal counts of sensory ganglia in the trkC mutant mice reveal less severe losses than those in NT-3 null mutant mice, strongly suggesting that NT-3, in vivo, may signal through receptors other than trkC. Mice lacking either NT-3 or all trkC receptor isoforms die in the early postnatal period. Histological examination of trkC-deficient mice reveals severe cardiac defects such as atrial and ventricular septal defects, and valvular defects including pulmonic stenosis. Formation of these structures during development is dependent on cardiac neural crest function. The similarities in cardiac defects observed in the trkC and NT-3 null mutant mice indicate that the trkC receptor mediates most NT-3 effects on the cardiac neural crest.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: ABL-Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702. e-mail: tessarol{at}ncifcrf.gov.
↵ § Present address: Department of Neurological Surgery and The Miami Project, University of Miami School of Medicine, Miami, FL 33136.
↵ ** Present address: The University of Texas, Southwestern Medical Center, Dallas, TX 75235.
ABBREVIATIONS:

NGF,

nerve growth factor;

BDNF,

brain-derived neurotrophic factor;

NT-3,

neurotrophin-3;

DRG,

dorsal root ganglia