Inactivation of one copy of the mouse neurotrophin-3 gene induces cardiac sympathetic deficits.

Inactivation of one copy of the mouse neurotrophin-3 gene induces cardiac sympathetic deficits.

Story G M; DiCarlo S E; Rodenbaugh D W; Dluzen D E; Kucera J; Maron M B; Walro J M

Physiological genomics

2000

2000-04

Whether two copies of the neurotrophin-3 (NT3) gene are necessary for proper development of cardiac sympathetic innervation was investigated in mice carrying a targeted inactivation of the NT3 gene. Heterozygous (+/-) and null (-/-) mutant mice had fewer stellate ganglion neurons than did wild-type (+/+) mice at postnatal day 0 (P0 or birth), and this deficit was maintained between adult (P60) +/- and +/+ mice. The sympathetic innervation of the heart matured postnatally in +/+ and +/- mice. Tyrosine hydroxylase (TH)-positive axons were restricted largely to the epicardium at P0, were concentrated around large blood vessels in the myocardium at P21, and were present among cardiac myocytes at P60. Cardiac norepinephrine (NE) concentrations paralleled the growth of the sympathetic axons into the heart. NE concentrations were equivalent among +/+, +/-, and -/- mice at birth, but differences between +/- and +/+ mice increased with age. Adult +/- mice also exhibited lower resting heart rates and sympathetic tonus than +/+ mice. Thus deletion of one copy of the NT3 gene translates into anatomical, biochemical, and functional deficits in cardiac sympathetic innervation of postnatal mice, thereby indicating a gene-dosage effect for the NT3 gene.

*Gene Dosage; Aging/metabolism; Animals; Axons/metabolism; Body Weight/genetics; Cell Count; Coronary Vessels/innervation; Heart Rate/genetics; Heart/*innervation; Heterozygote; Homozygote; In Situ Nick-End Labeling; Knockout; Mice; Muscle Tonus/genetics; Mutant Strains; Myocardium/cytology/*metabolism; Neurotrophin 3/deficiency/*genetics; Norepinephrine/metabolism; Organ Size/genetics; Stellate Ganglion/cytology; Sympathetic Nervous System/cytology/*growth & development/metabolism; Tyrosine 3-Monooxygenase/metabolism

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