PubMed · 8105288
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E R Greenberg, T A Stukel, J A Baron, D H Freeman. 1993-10-23. Statistical methods in research.. https://doi.org/10.1016/0140-6736(93)92911-c
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To overcome the genetic and interindividual variability frequently noted in complex phenotypes, we used echocardiographic selection to develop a substrain of myosin light chain (MLC)-Ras (RAS) transgenic mice with an enhanced ventricular hypertrophic phenotype. These echo-selected mice were then compared with wild-type (WT) animals and a pressure overload hypertrophy model (transverse aortic constriction; TAC). Echocardiography demonstrated increased wall thickness in RAS compared with the other groups. We developed novel miniaturized physiological technology to quantitatively identify in vivo intraventricular gradients; increased systolic Doppler velocity was seen in the left ventricle (LV) in 69% of RAS vs. none of WT or TAC. Intracavitary pressure gradients were present in 3 of 10 RAS vs. none of TAC or WT. Passive diastolic LV stiffness was not different among the three groups. Myofibrillar disarray was present in all RAS animals and was significantly more extensive (21.7% area fraction) than in TAC (1.5%) or WT (0.0%). RAS mice had selective induction of natriuretic peptide genes in the LV, a pattern distinct from that induced by pressure overload. Juvenile mortality was significantly increased in the offspring of echo-selected RAS parents. We conclude that adaptation of echocardiography to the mouse permits selection for cardiac phenotypes, and that selectively inbred MLC-Ras transgenic mice faithfully reproduce the molecular, physiological, and pathological features of human hypertrophic cardiomyopathy (HCM). Because previous studies support the concept that hypertrophy in human HCM is secondary to dysfunction created by sarcomeric protein mutations, the current studies suggest that Ras-dependent pathways might play a similar role in forms of human HCM.
To examine the physiological role of the Fyn tyrosine kinase in neurons, we generated transgenic mice that expressed a fyn cDNA under the control of the calcium/calmodulin-dependent protein kinase IIalpha promoter. With this promoter, we detected only low expression of Fyn in the neonatal brain. In contrast, there was strong expression of the fyn-transgene in neurons of the adult forebrain. To determine whether the impairment of long-term potentiation (LTP) observed in adult fyn-deficient mice was caused directly by the lack of Fyn in adult hippocampal neurons or indirectly by an impairment in neuronal development, we generated fyn-rescue mice by introducing the wild-type fyn-transgene into mice carrying a targeted deletion in the endogenous fyn gene. In fyn-rescue mice, Schaffer collateral LTP was restored, even though the morphological abnormalities characteristic of fyn-deficient mice were still present. These results suggest that Fyn contributes, at least in part, to the molecular mechanisms of LTP induction.
Superoxide dismutases (SODs) protect cells from damage by oxygen free radicals. Manganese (Mn) SOD is preferentially induced in terminally differentiating cells; induction of copper-zinc (CuZn) SOD is more closely associated with postnatal exposure to environmental sources of oxygen free radicals. The purpose of this study was to investigate ontogenetic changes in immunoreactivity for MnSOD and CuZnSOD relative to the expression of markers of neuronal and chemosensory differentiation in olfactory and vomeronasal receptor neurons (ORNs and VRNs, respectively), which mature with different time courses. Immunoreactivity for both SODs was detected in rat ORNs at embryonic day (E) 14, the earliest time point investigated, but not until E16 in vomeronasal neuroblasts. ORNs also expressed the neuronal marker protein gene product (PGP) 9.5 and the chemosensory cell marker olfactory marker protein (OMP) at E14; vomeronasal neuroblasts expressed PGP 9.5 at E16 but were not immunoreactive for OMP until postnatal day (P) 2. Immunoreactivity for MnSOD in ORNs and VRNs generally increased pre- and postnatally to a maximum at P11. Immunoreactivity for CuZnSOD did not increase markedly until after birth, reaching maximal levels at P11-P24. Within ORNs and VRNs, the most intense immunoreactivity was localized in the dendritic and supranuclear regions. The results indicate that in ORNs and VRNs, increases in MnSOD immunoreactivity during ontogeny parallel the ongoing differentiation and maturation of chemosensory receptor neurons; in contrast, the induction of immunoreactivity for CuZnSOD is associated with postnatal exposure to the ambient oxygen and xenobiotic environment.