1. Williams, R.W., Strom, R.C., Rice, D.S. & Goldowitz, D. Genetic and environmental control of variation in retinal ganglion cell number in mice. J. Neurosci. 16, 7193-7205 (1996).
2. Haug, H. Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: a stereological investigation of man and his variability and a comparision with some mammals (primates, whales, marsupials, insectivores, and one elephant). Am. J. Anat. 180, 126-142 (1987).
3. Williams, R.W. & Herrup, K. The control of neuron number. Annu. Rev. Neurosci. 11, 423-453 (1988).
4. Finlay, B.L. & Darlington, R.B. Linked regularities in the development and evolution of mammalian brains. Science 268, 1578-1584 (1995).
5. Curcio, C.A., Sloan Jr., K.A., Packer, O., Hendrickson, A.E. & Kalina, R.E. Distribution of cones in human and monkey retina: individual variability and radial asymmetry. Science 236, 576-582 (1987).
6. Gilissen, E. & Zilles, K. The calcarine sulcus as an estimate of the total volume of the human striate cortex: a morphometric study of reliability and intersubject variability. J. Brain Res. 37, 57-66 (1996).
7. Lai, C., Lyman, R.F., Long, A.D., Langley, C.H. & Mackay, T.F.C. Naturally occurring variation in bristle number and DNA polymorphisms at the Scabrous locus of Drosophila melanogaster. Science 266, 1697-1702 (1994).
8. Tanksley, S.D. Mapping polygenes. Annu. Rev. Genet. 27, 205-233 (1993).
9. Mackay, T.F.C. The genetic basis of quantitative variation: numbers of sensory bristles in Drosophila melanogaster as a model system. Trends Genet. 11, 464-470 (1995).
10. Strom, R.C., Goldowitz, D. & Williams, R.W. Mapping quantitative trait loci that control retinal ganglion cell number using F2 intercross progeny. Soc. Neurosci. Abst. 22, 518 (1996).
11. Hegmann, J.P. & Possidente, B. Estimating genetic correlations from inbred strains. Behav. Genet. 11, 103-114 (1981).
12. Watkins-Chow, D., Roller, M., Newhous, M.M., Camper, S.A. & Buchberg, A.M. Mouse Chromosome 11. Mamm. Genome 6, S201-220 (1996).
13. Williams, R.W., Strom, R.C. & Goldowitz, D. Mapping quantitative trait loci that control normal variation in brain weight in the mouse. Soc. Neurosci. Abst. 22, 519 (1996).
14. Lynch, M. & Walsh, B. in Fundamentals of Quantitative Genetics (http://nitro.biosci.arizona.edu/zbook/book.html) , (Sinauer Assoc., San Francisco, in the press).
15. Williams, R.W., Cavada, C. & Reinoso-Suarez, F. Rapid evolution of the visual system: A cellular assay of the retina and dorsal lateral geniculate nucleus of the Spanish wildcat and the domestic cat. J. Neurosci. 13, 208-228 (1993).
16. Zamenhof, S. & van Marthens, E. Neonatal and adult brain parameters in mice selected for adult brain weight. Dev. Psychobiol. 9, 587-593 (1978).
17. Zhou, G. & Williams, R.W. Mapping genes that control variation in eye weight, retinal area, and retinal cell density. Soc. Neurosci. Abst. 23, (in the press).
18. Buck, K.J., Metten, P., Belknap, J.K. & Crabbe, J.C. Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J. Neurosci. 17, (in the press).
19. Kanes, S. et al. Mapping the genes for haloperidol-induced catalepsy. J. Pharmacol. Exp. Ther. 277, 1016-1025 (1996).
20. Plomin, R., McClearn, G.E., Gora-Maslak, G. & Neiderhiser, J.M. Use of recombinant inbred strains to detect quantitative trait loci associated with behavior. Behavior Genetics 21, 99-116 (1991).
21. Dains, K., Hitzeman, B. & Hitzeman, R. Genetics, neuroleptic-response and the organization of cholinergic neurons in the mouse striatum. J. Pharmacol. Exp. Therap. 279, 1430-1438 (1996).
22. Buchberg, A.H. A comprehensive genetic map of murine chromosome 11 reveals extensive linkage conservation between mouse and human. Genetics 122, 153-161 (1989).
23. Beach, D.H. & Jacobson, M. Influence of thyroxine on cell proliferation in the retina of the clawed frog at different ages. J. Comp. Neurol. 183, 615-624 (1979).
24. Bermingham-McDonogh, O., McCabe, K.L. & Reh, T.A. Effects of GGF/neuregulins on neuronal survival and neurite outgrowth correlate with erbB2/neu expression in developing rat retina. Development 122, 1427-1438 (1996).
25. Hoskins, S.G. & Grobstein, P. Induction of the ipsilateral retinothalamic projection in Xenopus laevis by thyroxine. Nature 307, 730-733 (1984).
26. Hyatt, G.A. et al. Retinoic acid establishes ventral retinal characteristics. Development 121, 195-204 (1996).
27. Hyatt, G.A., Schmitt, E.A., Marsh-Armstrong, N.R. & Dowling, J.E. Retinoic acid-induced duplication of the zebrafish retina. Proc. Natl. Acad. Sci. USA 89, 8293-8297 (1992).
28. Kelley, M., Turner, J.K. & Reh, T.A. Ligands of steroid/thyroid receptors induce cone photoreceptors in vertebrate retina. Development 121, 3777-3785 (1995).
29. Kelley, M.W., Turner, J.K. & Reh, T.A. Retinoic acid promotes differentiation of photoreceptors in vitro. Development 120, 2091-2102 (1994).
30. Stenkamp, D.L., Gregory, J.K. & Adler, R. Retinoid effects in purified cultures of chick embryo retina neurons and photoreceptors. Invest. Ophth. & Vis. Sci. 34, 2425-2436 (1993).
31. Hoskins, S.G. Control of the development of the ipsilateral retinothalamic projection in Xenopus laevis by thyroxine: results and speculation. J. Neurobiol. 17, 203-229 (1985).
32. Meyer, D. & Birchmeier, C. Distinct isoforms of neuregulin are expressed in mesenchymal and neuronal cells during mouse development. Proc. Natl. Acad. Sci. USA 91, 1064-1068. (1994).
33. Strom, R.C., Williams, R.W. & Goldowitz, D. Developmental mechanisms responsible for strain differences in the retinal ganglion cell population. Soc. Neurosci. Abst. 21, 1523 (1995).
34. Williams, M.A., Pinon, L.G.P., Linden, R. & Pinto, L.H. The Pearl mutation accelerates the schedule of natural cell death in the early postnatal retina. Exp. Brain Res. 82, 393-400 (1990).
35. Gan, L. et al. Pou domain factor Brn-3b is required for the development of a large set of retinal ganglion cells. Proc. Natl. Acad. Sci. USA 93, 3920-3925 (1996).
36. Grindley, J., Davidson, D. & Hill, R. The role of Pax-6 in eye and nasal development. Development 121, 1433-1442 (1995).
37. Packer, S.O. The eye and skeletal effects of two mutant alleles at the microophthalmia locus of Mus musculus. J. Exp. Zool. 1, 21-45 (1967).
38. Steingrimsson, E. et al. Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences. Nature Genet. 8, 256-263 (1994).
39. Burmeister, M. et al. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genet. 12, 376-384 (1996).
40. Tomita, K. Mammalian hairy and enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16, 723-734 (1996).
41. Rice, D.S. et al. Mapping the Bst mutation on mouse chromosome 16: a model for human optic atrophy. Mamm. Genome 6, 546-548 (1995).
42. Austin, C.P., Feldman, D.E., Ida, J.A. & Cepko, C.L. Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. Development 121, 3637-3650 (1995).
43. Sicinski, P. & Weinberg, R. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621-630 (1995).
44. Johnson, J.E., Barde, Y.A., Schwab, M. & Thoenen, M. Brain-derived neurotrophin factor supports the survival of cultured rat retinal ganglion cells. J. Neurosci. 6, 3031-3038 (1986).
45. Cepko, C.L. & Guillemot, F. Retinal fate and ganglion cell differentiation are potentiated by acidic FGF in an in vitro assay of early retinal development. Development 114, 743-754 (1992).
46. Ribacchi, S.A., Ensini, M., Bonfanti, L., Bravina, A. & Maffei., L. Nerve growth factor reduces apoptosis of axotomized retinal ganglion cells in the neonatal rat. Neuroscience 63, 969-973 (1994).
47. Bonfanti, L. et al. Protection of retinal ganglion cells from natural and axotomy-incuded cell death in neonatal transgenic mice overexpressing bcl-2. J. Neurosci. 16, 4186-4194 (1996).
48. Burne, J.F., Staple, J.K. & Raff, M.C. Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons. J. Neurosci. 16, 2064-2073 (1996).
49. Martinou, J.-C. et al. Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13, 1017-1030 (1994).
50. Lufkin, T. et al. High postnatal lethality and testis degeneration in retinoic acid receptor a mutant mice. Proc. Natl. Acad. Sci. USA 90, 7225-7229 (1993).
51. Armstrong, E. Relative brain size and metabolism in mammals. Science 220, 1302-1304 (1983).
52. Llinas, R.R. & Walton, K.D. in Synaptic Organization of the Brain (ed G.M. Shepherd) 214-245 (Oxford Univ. Press, New York, 1990).
53. Rice, D.S., Williams, R.W. & Goldowitz, D. Genetic control of retinal projections in inbred strains of albino Mice. J. Comp. Neurol. 354, 459-469 (1995).
54. Williams, R.W., Goldowitz, D. & Strom, R.C. Brain weight in relation to body weight, age and sex: A multiple regression analysis. Soc. Neurosci. Abst. 23, (in the press).
55. Haley, C.S. & Knott, S.A. A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69, 315-324 (1992).
56. Jansen, R.C. Interval mapping of multiple quantitative trait loci. Genetics 135, 205-211 (1993).
57. Tinker, N.A. & Mather, D.E. Methods for QTL analysis with progeny replicated in multiple environments. J. Quant. Trait Analysis (1996).
58. Manly, K. (1996). MapManager QT. (http://mapmgr.roswellpark.org/mapmgr.html).
59. Churchill, G.A. & Doerge, R.W. Empirical threshold values for quantitative trait mapping. Genetics 138, 963-971.
Note 1. The first two modes in Figure 1 can be fit neatly by a single locus additive model with the substitution of a pair of DBA/2J alleles adding +10,000 cells to the base population of 54,000. The third mode (BXD5 and BXD32) can be fit by considering one or two additional QTLs (probably a positive alleles from the C57BL/6J parental strain) and by assuming significant non-linear epistatic interactions among loci. All 1-locus, 2-locus, and 3-locus models that we explored required effects of +5,000 to +6,000 per DBA/2J allele to obtain a good fit.
Note 2. While the advantages of RI strains for mapping quantitative traits that are subject to substantial non-genetic variance have been clear for many years, RI strains have rarely been used as the principal method to map QTLs. The main obstacle has been that the number of RI strains is usually too small to define QTLs with phenotypes that are normally distributed or controlled by large numbers of factors.