Knockouts cardiac phenotypes

Cardiac Phenotypes in Male a,-Adrenergic Receptor Subtype Knockouts... 

Mice that lack caspase-1, -11, or -12 do not have a significant decrease in viability and have no overt consequence on their development [57-59,69,72]. In contrast, caspase-3 and/or -9 ablation results in retarded developmental apoptosis and has a tremendous impact on animals viability and phenotype [61, 67]. Similarly, caspase-8 knockout mice die in utero and are characterized by impaired formation of cardiac muscle and marked abdominal congestion with reduction of the number of hematopoietic precursors [65], The size of the heart was reported to be almost normal, but the developing ventricular musculature was thin and sometimes similar to early mesenchyme. The trabeculae were thin and disorganized. Cultured fibroblasts from caspase-8 mice were resistant to death receptor-mediated apoptosis. These findings indicate that caspase-8 plays an important role in death induction by several receptors of Fas/TNF/NGF family. Similarly, Sakamaki et al. [66] described that protease-deficient caspase-8 mutant mice died in utero due to heart rupture which they believe was due to cardiomyocyte apoptosis. 

The NRG1-ICD is essential for surface expression of Type I Nrg l(Liu et al., 1998a). In vitro experiments demonstrate that Type I isoforms of NRG 1 lacking an intact intracellular domain fail to be expressed at the cell surface, and therefore fail to release soluble growth factor. Because the Type I NRG1 isoform is required for cardiac development, the so-called transmembrane mutant animals, the pan-knockout animals, and the Ig-mutant animals (in which the Ig-like domain common to all Type I and Type II isoforms is disrupted) all show the same embryonic lethal phenotype. 

Cathepsin L-deficient mice show decreased levels of enkephalin in the brain, with reduction by approximately one half (22). In addition, enkephalin brain levels are also reduced by about one half in PC2-deficient mice (28). These results support dual roles for both cathepsin L and PC2 in enkephalin production. Ongoing studies indicate multiple neuropeptides that are substantially decreased by more than 50% in the brain and endocrine tissues of cathepsin L knockout mice (Eunkelstein et al., submitted for publication). With the observed alterations in brain neuropeptides, it will be of interest in future studies to assess the behavioral effects of the loss of neuropeptides in cathepsin L knockout mice. Cathepsin L knockout mice are viable and show phenotypes of hair loss and cardiac myopathy (29, 30). The mechanism for these functional effects of cathepsin L deficiency could possibly involve neuropeptides. New and continued investigations of neuropeptides in cathepsin L knockout mice will provide knowledge of the relative roles of cathepsin L in the production of particular neuropeptides. 

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