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R.W. Nickells, Y. Li, S.J. Semaan, V. Babcic, C.L. Schlamp; Autosomal Dominant Inheritance of Ganglion Cell Resistance to Optic Nerve Crush in Inbred Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3576.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Previously (Li et al ARVO 2003 abstract 1131) we identified inbred mouse lines either resistant (DBA/2J) or susceptible (BALB/cByJ) to ganglion cell death stimulated by optic nerve crush. Here, we investigated the distribution of the resistant phenotype in the F1, F1 backcross, and F2 generations of mice produced from DBA/2J and BALB/cByJ parents and the potential of Bax as a candidate gene that affects the cell death phenotype. Methods:DBA/2J and BALB/cByJ parental mice were purchased from JAX. F1 mice produced from crossing the parental lines were backcrossed onto BALB/cByJ mice or interbred to produce F2 mice. Mice from the parental lines, F1, F1 backcross, and F2 generations were subjected to optic nerve crush at 8 wks of age. Mice were sacrificed 2 wks after crush and cell loss in the GCL was calculated from Nissl–stained wholemounted retinas from both the experimental and control eyes. Bax sequence was determined from neuronal cDNAs isolated from each line. Neuronal Bax mRNA levels were quantified by RNase Protection Assays (RPA). Bax alleles were determined using polymorphic markers that map at position 23 on Chr 7 (D7Mit27). Results:DBA/2J mice exhibited a significantly more resistant phenotype than BALB/cByJ mice (t–test, P=3.8E–08, n=31). An F1 cross of these two lines yielded a resistant phenotype (P=0.178 vs DBA/2J; P=0.0007 vs BALB/cByJ, n=28). F1 x BALB/cByJ mice had a susceptible phenotype (P=2.2E–06 vs DBA/2J; P=0.15 vs BALB/cByJ, n=55), while F2 mice (F1 x F1) exhibited an intermediate phenotype with a bias toward resistance (P=0.017 vs DBA/2J; P=0.006 vs BALB/cByJ, n=56). The Wright Formula calculation using data from the F1 and recurrent backcross parental line yielded a value of 1.3. Sequence analysis of Bax cDNAs isolated from each line showed the same predicted amino acid sequence, while RPA showed equal levels of Bax mRNA. Mapping experiments indicated that the Bax allele did not co–segregate with the cell death phenotype in either the F1 backcross or F2 mice (ANOVA, P>0.10, n=107). Conclusions:Wright formula calculations and the inheritance pattern of the resistant phenotype suggested that DBA/2J mice carry a single dominant allele that confers resistance. Bax was excluded as this allele.
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