| First Author | Vadasz C | Year | 1990 |
| Journal | Mouse Genome | Volume | 88 |
| Pages | 16-8 | Mgi Jnum | J:59316 |
| Mgi Id | MGI:1351383 | Citation | Vadasz C, et al. (1990) Development of congenic recombinant inbred neurological animal model lines. Mouse Genome 88:16-8 |
| abstractText | Full text of Mouse Genome contribution: Development of Congenic Recombinant Inbred Neurological Animal Model Lines. Understanding the neural substrate of behavior is one of the ultimate goals in neuroscience. Genetic variability in the central nervous system has been recognized as a potentially important tool in this endeavour. However, analysis of genetically based correlations between quantitative neurobiological and behavioral traits has been difficult. Factors limiting progress in the field have included the oligo- or polygenic nature of most behavioral and neural phenotypes, phenocopy, genetic heterogeneity, and intergenic and genotype environment interactions in crossbreeding studies. To circumvent some of these obstacles in the genetic analysis of catecholamine neurotransmitter mechanisms, we initiated a long term study (NIH NS-19788) based on our prior work (Vadasz et al., 1982) to transfer genes that influence the activity of mesencephalic tyrosine hydroxylase, the rate limiting enzyme in catecholamine biosynthesis, to the same genetic background. The transfer of genes was carried out by backcross-intercross cycles with concomitant selection for mesencephalic tyrosine hydroxylase (TH/MES) . Selection for a trait can demonstrate the presence of, or a relationship with, a second trait by indicating the correlated changes in the second trait as a response to selection for the first. The selected lines were replicated to test the generality of the response to selection and to substantially decrease the probability of chance covariation. By using animals with a similar genetic background, the interactive genetic effects can be minimized. This allows (1) identification of individual effects of genes, and (2) easier detection of covariation between complex traits caused by pleiotropy or linkage of genes. This approach yields animal lines with similar genetic background differing only in a small number of genes with relatively large effects on TH/MES. Construction of congenic lines with high and low TH/MES was based on (B6XC) F2 and (B6XI) F2 foundation populations, respectively, derived from C57BL/6ByJ (B6), BALB/cJ (C), and CXBI/ByJ (I). Prior to establishing the foundation populations, B6, C, and I have been characterized as expressing intermediate, high and low TH/MES (Vadasz et al., 1982; cf. also Vadasz et al., 1987) . A breeding program of backcross-intercross cycles with concomitant selection for high or low TH/MES was followed. The symbol to designate the developing congenic lines combines the shortened symbols of the background strain (B6) followed by a period, the differential-source-strain symbol (C or I), the number of the accomplished backcrosses and intercrosses (bn in), and the name of the replicate (alpha or beta) . After having sired viable offspring, males were subjected to behavioral tests, and were killed. Their TH activity values were then determined. Offspring of selected animals were used to establish new mating pairs. The following table shows mean TH/MES values of offspring-generations of selected fathers, and the probability of incrosses at any nonlinked, nonselected locus. MESENCEPHALIC TH ACTIVITY* IN DEVELOPING CONGENIC LINES Cycle: M2**; B6.C alpha(n): 3.34(93); beta(n): 3.53(88); B6.I alpha(n): 2.95(95); beta(n): 2.99(91); P: 0.594. Cycle: M3; B6.C alpha(n): 3.41(148); beta(n): 3.43(165); B6.I alpha(n): 2.85(152); beta(n): 2.83(147); P: 0.793. Cycle: M4; B6.C alpha(n): 3.34(220); beta(n): 3.46(189); B6.I alpha(n): 2.86(172); beta(n): 2.72(179); P: 0.896. Cycle: M5; B6.C alpha(n): 3.47(140); beta(n): 3.37(125); B6.I alpha(n): 2.74(130); beta(n): 2.86(124); P: 0.948. * nmol DOPA/substantia nigra-A8-A10 area; n number of animals ** Mn number of backcross-intercross cycles. In M3 and M4 two intercrosses followed each backcross. In the second phase of this work, a regular system of brother-sister matings has been applied to fix these genes and to produce congenic recombinant inbred (CRI) lines. Some of the offspring of b4 i5 mice (cycle M5) have already been subjected to strict brother-sister mating for up to 5 successive generations, establishing 28 developing M5-CRI lines, while the rest of the offspring entered cycle M6. To create sets of M6-CRI lines representing B6.C-alpha, B6.C-beta, B6.I-alpha and B6. I-beta replicates, offspring of b5 i7 mice (cycle M6) are used employing a regular system of brother-sister mating as above. Inbreeding will be continued in both M5- and M6-CRI lines for 20-25 successive brother-sister matings. Development of sets of congenic recombinant inbred neurological animal model lines with different mesencephalic DA systems provides an analytical tool for mechanism-oriented experimentation. Different levels of mesencephalic TH activity, or, implicitly, the number of DA neurons (Ross et a1., 1976 ; Baker et al., 1980), will be available for study in the congenic recombinant inbred and background lines in genetically fixed forms, while other genetically unrelated brain and behavioral characters will be similar in all individuals. REFERENCES Vadasz, C., Baker, H., Joh, T.H., Lajtha, A., Reis, D.J. (1982) The inheritance and genetic correlation of tyrosine hydroxylase activities in the CXB recombinant inbred mouse strains. Brain Res. 234, 1-9. Vadasz, C., Sziraki, I., Murthy, L.R., Badalamenti, A.F., Lajtha, A. (1987) Genetic determination of mesencephalic tyrosine hydroxylase activity in the mouse. J. Neurogenet. 4, 241-252. |
