Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development

Abstract

Neurotrophin 3 (Nt3) is one of five neurotrophin growth factors which shape the development of the nervous system by regulating neuronal survival and differentiation. Peripheral neuronal subpopulations expressing the TrkC receptor tyrosine kinase respond to Nt3 with enhanced survival, mitogenesis or cell migration and these neurons are lost in homozygous Nt3 null (-/-) mutant mice. The unexplained perinatal lethality in the Nt3-/- mice, however, suggests a wider function for this neurotrophin. Here we report that Nt3 is essential for the normal development of atria, ventricles, and cardiac outflow tracts. Histological and echocardiographic image analysis of Nt3-/- animals reveal severe cardiovascular abnormalities including atrial and ventricular septal defects, and tetralogy of Fallot, resembling some of the most common congenital malformations in humans. The observed defects are consistent with abnormalities in the survival and/or migration of cardiac neural crest early in embryogenesis and establish an essential role for neurotrophin 3 in regulating the development of the mammalian heart.

Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample

“…Of these, the genes encoding ionotropic Nmethyl D-aspartate glutamate receptor subunit 2B (GRIN2B), neurotrophin 3 (NTF3), GABA-A receptor-associated protein-like protein 1 (GABARAPL1) and a cluster of subunits for a taste receptor represent plausible candidates for a future association study in view of their biological function(s) and the biochemical pathways involved in drug addiction. [46][47][48][49][50] Although several association studies have been conducted to investigate the association of NTF3 and GRIN2B with schizophrenia and alcohol dependence, the results have been inconclusive. [51][52][53][54] Regarding potential candidate genes from other regions, we will not discuss these in the present report because (1) they have been reported previously for possible association with nicotine and/or alcohol dependence in independent sample; (2) potential candidate genes for a few chromosomal regions were discussed in our recent report based on the AA sample; 20 and/or (3) a limited number of candidate genes are obvious on the basis of their functionality unless we are able to demonstrate their association experimentally, a consideration which is well beyond the scope of this report.…”

The noncatalytic TrkCNC2 receptor is cleaved by metalloproteases upon neurotrophin-3 stimulation

“…Interestingly, NT-3 as well as TrkC null mutant mice suffer from cardiac malformation (Donovan et al, 1996;Tessarollo et al, 1997). Since these deficiencies are not observed in TrkC catalytic receptor mutants, it suggests that NT-3 effects are mainly mediated during heart development by noncatalytic TrkC receptors that are highly expressed in the cardiovascular system (Menn et al, 1998).…”

Distinct cardiac malformations caused by absence of connexin 43 in the neural crest and in the non-crest neural tube

“…Furthermore, the Cx43-null mutant phenotype, characterized by infundibular bulging without septation defects, differs from other murine genetic models that affect CNC function. Genetic models including those with mutations in or knockouts of Pax3, neurotrophin 3/TrkC, TGF␤ receptor type II, BMP4, BMP receptor IA, endothelin 1 and combinations of retinoic acid receptors (Choudhary et al, 2006;Donovan et al, 1996;Epstein et al, 2000;Kurihara et al, 1995;Liu et al, 2004;Mendelsohn et al, 1994;Stottmann et al, 2004;Youn et al, 2003) commonly cause OFT septation defects similar to those resulting from chick NC ablation. Thus, during development, Cx43 may be required in tissues that contribute to heart formation other than or in addition to the CNC (Li et al, 2002;Walker et al, 2005).…”